Thio-substituted arylmethanesulfinyl derivatives

ABSTRACT

The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions of compounds of Formula (A):  
                 
 
wherein Ar, X, Y, R 1 , R 2 , R 3 , and q are as defined herein; and their use in the treatment of diseases, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson&#39;s disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder (“ADHD”), enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of pending U.S. Provisional ApplicationSer. No. 60/568,991, filed May 7, 2004 and European Patent ApplicationNumber 04290983.8, filed Apr. 13, 2004. The disclosures of these priorapplications is incorporated herein by reference in their entireties forall purposes.

FIELD OF THE INVENTION

The present invention is related to chemical compositions, processes forthe preparation thereof and uses of the composition. Particularly, thepresent invention relates to compositions of compounds of Formula (A):

and their use in the treatment of diseases, including treatment ofsleepiness, promotion and/or improvement of wakefulness, preferablyimprovement of wakefulness in patients with excessive sleepinessassociated with narcolepsy, sleep apnea, preferably obstructive sleepapnea/hypopnea, and shift work disorder; treatment of Parkinson'sdisease; Alzheimer's disease; cerebral ischemia; stroke; eatingdisorders; attention deficit disorder (“ADD”), attention deficithyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue,preferably fatigue associated with cancer or neurological diseases, suchas multiple sclerosis and chronic fatigue syndrome; stimulation ofappetite and weight gain and improvement of cognitive dysfunction.

BACKGROUND OF THE INVENTION

The compounds disclosed herein are related to the biological andchemical analogs of modafinil. Modafinil, C₁₅H₁₅NO₂S, also known as2-(benzhydrylsulfinyl) acetamide, or 2-[(diphenylmethyl) sulfinyl]acetamide, a synthetic acetamide derivative with wake-promotingactivity, has been described in French Patent No. 78 05 510 and in U.S.Pat. No. 4,177,290 (“the '290 patent”). It has been approved by theUnited States Food and Drug Administration for use in the treatment ofexcessive daytime sleepiness associated with narcolepsy. Methods forpreparing modafinil and several derivatives are described in the '290patent. The levorotatory isomer of modafinil, along with additionalmodafinil derivatives are described in U.S. Pat. No. 4,927,855, and arereported to be useful for treatment of hypersomnia, depression,Alzheimer's disease and to have activity towards the symptoms ofdementia and loss of memory, especially in the elderly.

Modafinil has also been described as a useful agent in the treatment ofParkinson's disease (U.S. Pat. No. 5,180,745); in the protection ofcerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in thetreatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776);and in the treatment of sleep apneas and disorders of central origin(U.S. Pat. No. 5,612,379). In addition, modafinil may be used in thetreatment of eating disorders, or to promote weight gain or stimulateappetite in humans or animals (U.S. Pat. No. 6,455,588), or in thetreatment of attention deficit hyperactivity disorder (U.S. Pat. No.6,346,548), or fatigue, especially fatigue associated with multiplesclerosis (U.S. Pat. No. 6,488,164). U.S. Pat. No. 4,066,686 describesvarious benzhydrylsulphinyl derivatives as being useful in therapy fortreating disturbances of the central nervous system.

Several published patent applications describe derivative forms ofmodafinil and the use of modafinil derivatives in the treatment ofvarious disorders. For example, PCT publication WO 99/25329 describesvarious substituted phenyl analogs of modafinil as being useful fortreating drug-induced sleepiness, especially sleepiness associated withadministration of morphine to cancer patients. U.S. Pat No. 5,719,168and PCT Publication No. 95/01171 describe modafinil derivatives that areuseful for modifying feeding behavior. PCT Publication No. 02/10125describes several modafinil derivatives of modafinil, along with variouspolymorphic forms of modafinil.

Additional publications describing modafinil derivatives include U.S.Pat. No. 6,492,396, and PCT Publication No. WO 02/10125.

Terauchi, H, et al. described nicotinamide derivatives useful as ATP-aseinhibitors (Terauchi, H, et al, J. Med. Chem., 1997, 40, 313-321). Inparticular, several N-alkyl substituted 2-(Benzhydrylsulfinyl)nicotinamides are described.

U.S. Pat. Nos. 4,980,372 and 4,935,240 describebenzoylaminophenoxybutanoic acid derivatives. In particular, sulfidederivatives of modafinil containing a phenyl and substituted phenyllinker between the sulfide and carbonyl, and a substituted aryl in theterminal amide position, are disclosed.

Other modafinil derivatives have been disclosed wherein the terminalphenyl groups are constrained by a linking group. For example, in U.S.Pat. No. 5,563,169, certain xanthenyl and thiaxanthenyl derivativeshaving a substituted aryl in the terminal amide position are reported.

Other xanthenyl and thiaxanthenyl derivatives are disclosed in Annis, I;Barany, G. Pept. Proc. Am. Pept. Symp. 15^(th) (Meeting Date 1997)343-344, 1999 (preparation of a xanthenyl derivative of Ellman'sReagent, useful as a reagent in peptide synthesis); Han, Y.; Barany, G.J. Org. Chem., 1997, 62, 3841-3848 (preparation of S-xanthenyl protectedcysteine derivatives, useful as a reagent in peptide synthesis); andEl-Sakka, I. A., et al. Arch. Pharm. (Weinheim), 1994, 327, 133-135(thiaxanthenol derivatives of thioglycolic acid).

Thus, there is a need for novel classes of compounds that possess thebeneficial properties. It has been discovered that a class of compounds,referred to herein as substituted thioacetamides, are useful as agentsfor treating or preventing various diseases or disorders disclosedherein.

SUMMARY OF THE INVENTION

The present invention in one aspect is directed to various novelcompounds of formula (A):

and its stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt forms thereof, wherein the constituentmembers are defined infra.

Another object of the present invention is to provide pharmaceuticalcompositions comprising the compounds of the present invention whereinthe compositions comprise one or more pharmaceutically acceptableexcipients and a therapeutically effective amount of at least one of thecompounds of the present invention, or a pharmaceutically acceptablesalt or ester form thereof.

Another object of the present invention is to provide methods oftreating or preventing diseases or disorders, including treatment ofsleepiness, promotion and/or improvement of wakefulness, preferablyimprovement of wakefulness in patients with excessive sleepinessassociated with narcolepsy, sleep apnea, preferably obstructive sleepapnea/hypopnea, and shift work disorder; treatment of Parkinson'sdisease; Alzheimer's disease; cerebral ischemia; stroke; eatingdisorders; attention deficit disorder (“ADD”), attention deficithyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue,preferably fatigue associated with cancer or neurological diseases, suchas multiple sclerosis and chronic fatigue syndrome; stimulation ofappetite and weight gain and improvement of cognitive dysfunction.

These and other objects, features and advantages of compounds of formula(A) will be disclosed in the following detailed description of thepatent disclosure.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides novel compounds offormula (A):

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, OR²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl C₂-C₆ alkenyl,            C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered            heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,            arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,            NR₂₁C(═O)R²², NR₂₁CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and            S(O)_(y)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR₂₂, NR₂₂S(O)₂,        C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C;    -   Y is C₁-C₆ alkylene; or        -   (C₁-C₄ alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;    -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10        membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered        heterocycloalkylene; wherein said arylene, heteroarylene,        cycloalkylene, and heterocycloalkylene groups are optionally        substituted with one to three R²⁰ groups;    -   R¹ is selected from H, C₆-C₁₀ aryl, NR¹²R¹³, NR₂₁C(═O)R¹⁴,        C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³,        OC(═O)NR¹²R¹³, NR₂₁S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and        NR²¹S(O)₂NR¹²R¹³;        -   wherein said aryl groups are optionally substituted with one            to three R²⁰ groups;    -   R² and R³ are each independently selected from from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered        heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR₂₁C(═O)R²²,        NR₂₁CO₂R²², OC(═O)NR²³R²⁴, NR₂₁C(═S)R²², and S(O)_(y)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said        alkyl and aryl groups are optionally substituted with one to        three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H, C₁-C₆        alkyl, preferably C₃-C₇ alkyl, and C₆-C₁₀ aryl; wherein said        alkyl and aryl groups are optionally substituted with one to        three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H,C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;        -   wherein said alkyl and aryl groups and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl;        -   wherein said alkyl, aryl and arylalkyl groups are optionally            substituted with one to three R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl        optionally substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl,        phenyl, 5 or 6 membered heteroaryl, arylalkyl, ═O, C(═O)R²²,        CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,        OC(═O)NR²³R²⁴, and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and        C₁-C₆ alkyl;    -   R²² at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   m is 0 or 1;    -   n is 0 or 1;    -   q is 0, 1, or 2;    -   y is 0, 1, or 2;    -   with the exclusion of the compounds wherein:        -   Y is C₂ alkylene substituted with one to three C₁-C₆            alkylene and/or NR²³R²⁴ and/or NR²¹CO₂R²²; and        -   R¹ is C(═O)NR¹²R¹³; or        -   Y is C₂ alkylene substituted with one to three (C₁-C₆)            alkyl; and        -   R¹ is phenyl optionally substituted with one to three groups            R²⁰; or        -   Y is CH₂—Z—(CH₂), wherein n=0 or 1, and Z is cyclopropyl or            cyclobutyl optionally substituted; and        -   R¹ is H or phenyl optionally substituted with one to three            groups R²⁰; or        -   Y is CH₂; and        -   R¹ is phenyl optionally substituted with one to three groups            R²⁰; or        -   Ar is a 5-10 membered heteroaryl group or a phenyl            optionally substituted with one to three groups selected            from CF₃, NR²¹C(═O)R²², NO₂ or CO₂H; and/or        -   X is S(O)_(y); and        -   Y=CH₂ or CH₂CH₂; and        -   R¹ is H.            and with the exclusion of the compounds:    -   N-[2,6-bis(1-methylethyl)phenyl]-2-[[4-(2-pyridinylmethoxy)phenyl]methyl]thio]-acetamide;    -   tetrahydro-2-[[{4-(phenylthio)phenyl]methyl}thio]acetyl]-2H-1,2-oxazine;        and    -   2-chloro-1-[3-[(methylsulfonyl)methyl]-4-nitrophenoxy]-4-(trifluoromethyl)-benzene        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

In a second embodiment, the present invention provides a compound offormula (I),

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, OR²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,            C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered            heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,            arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,            NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and            S(O)_(y)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²²,        NR²²S(O)₂C(R²²)₂, C(R²²)₂, CR²¹═CR²¹, C≡C;    -   Y is C₁-C₆ alkylene;        -   (C₁-C₄ alkylene)_(m)—Z¹—(C₁-C₄ alkylene)_(n);        -   C₁-C₄ alkylene-Z²—C₁-C₄ alkylene;            -   wherein said alkylene groups are optionally substituted                with one to three R²⁰ groups;    -   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered        heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered        heterocycloalkylene; wherein said arylene, heteroarylene,        cycloalkylene, and heterocycloalkylene groups are optionally        substituted with one to three R²⁰ groups;    -   Z² is O, NR^(10A), or S(O)_(y);    -   R¹ is selected from H, C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴,        C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³,        OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and        NR²¹S(O)₂NR¹²R¹³;        -   wherein said aryl groups are optionally substituted with one            to three R²⁰ groups;    -   R² and R³ are each independently selected from from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered        heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,        NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said        alkyl and aryl groups are optionally substituted with one to        three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;        -   wherein said alkyl and aryl groups are optionally            substituted with one to three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;        -   wherein said alkyl and aryl groups and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl and        arylalkyl groups are optionally substituted with one to three        R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl        optionally substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl,        phenyl, 5 or 6 membered heteroaryl, arylalkyl, ═O, C(═O)R²²,        CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,        OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and        C₁-C₆ alkyl;    -   R²² at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   m is 0 or 1;    -   n is 0 or 1;    -   q is 0, 1, or 2;    -   y is 0, 1, or 2;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

In another preferred embodiment of the invention, there are providedcompounds of formula (Ia)

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl, wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, OR²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, C₁-C₆ alkyl, phenyl, arylalkyl, and            C(═O)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²), C(R²²)₂O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂;    -   Y is C₁-C₆alkylene;        -   C₁-C₄ alkylene-Z¹—(C₁-C₄ alkylene)_(n); or        -   C₁-C₄ alkylene-Z²—C₁-C₄ alkylene;        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;    -   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered        heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered        heterocycloalkylene;    -   Z² is O, NR^(10A), or S(O);    -   R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,        C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,        NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;    -   R² and R³ are each independently selected from F, Cl, Br, I,        OR²², OR²⁵, NR²³ R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5        or 6 membered heteroaryl, arylalkyl, C(═O)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C(═O)R¹⁴, and S(O)_(y)R¹⁴;        -   wherein said alkyl groups are optionally substituted with            one to three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H, and        C₁-C₆ alkyl; wherein said alkyl groups are optionally        substituted with one to three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H, and C₁-C₆ alkyl, or R¹²and R¹³, together with the        nitrogen to which they are attached, form a 3-7 membered        heterocyclic ring;        -   wherein said alkyl and aryl groups and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl and        arylalkyl groups are optionally substituted with one to three        R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, phenyl, benzyl, ═O,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹CO₂R²²,        OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and        C₁-C₆ alkyl;    -   R²² at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, and C₁-C₆ alkyl, or R²³ and R²⁴, together with the        nitrogen to which they are attached, form a 3-7 membered        heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   n is 0 or 1;    -   y is 0, 1, or 2;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

An additional aspect of the present invention includes compounds offormula (A) and formulas (I) and (Ia) wherein Y is C₁-C₆ alkylene, C₁-C₄alkylene-Z¹—C₁-C₄ alkylene, or C₁-C₄ alkylene-Z²—C₁-C₄ alkylene, whereinsaid alkylene groups are optionally substituted with one to three C₁-C₆alkyl groups; Z¹ is CR²¹═CR²¹, C≡C, or phenyl; Z² is O, NR^(10A), orS(O)_(y); R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,and C(═O)NR¹²R¹³. In other aspects, Y is C₁-C₆ alkylene, or C₁-C₄alkylene-Z¹—C₁-C₄ alkylene. In additional aspects, Y is C₁-C₆ alkylene.In further aspects, R¹ is C(═O)NR¹²R¹³.

In certain aspects of the present invention, there are includedcompounds of formula (A) and formulas (I) and (Ia) where Ar is phenyl.Other aspects include compounds where Ar is napthyl. Other aspectsinclude compounds where Ar is thienyl. Other aspects include compoundswhere Ar is furyl.

In additional aspects of the present invention, there are includedcompounds of formula (A) and formulas (I) and (la) wherein Ar has any ofthe values of the previous embodiments and q is 1.

In other aspects of the present invention, there are included compoundsof formula (A) and formulas (I) and (Ia) where X is O, S(O)_(y), N(R¹⁰),OC(R²²)₂, C(R²²)₂NR²¹, C(═O)N(R²¹), S(O)₂NR²².

In additional aspects of the present invention, there are includedcompounds of formula (A) and formulas (I) and (Ia) where X is O,S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂NR²¹, C(═O)N(R²¹), S(O)₂NR²² and q is1.

Other aspects of the present invention include compounds of formula (A)and formulas (I) and (Ia) wherein Ar and X and q have any of the valuesof the previous embodiments, and Y is C₁-C₆ alkylene, particularly thosewhere Y is CH₂ or CH₂CH₂, and most particularly those where Y is CH₂.

Additional aspects of the present invention include compounds of formula(A) and formulas (I) and (Ia) wherein Ar, X and q have any of the valuesof the previous embodiments, and Y is (C₁-C₄ alkylene)_(m)—Z¹—(C₁-C₄alkylene)_(n) wherein Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 memberedheterocycloalkylene. Other aspects include those compounds where Y isC₁-C₄ alkylene-Z¹. Other aspects include those where Y is Z¹—C₁-C₄alkylene. Additional aspects include compounds where Y is C₁-C₄alkylene-Z—C₁-C₄ alkylene.

Further aspects of the present invention include compounds of formula(A) and formulas (I) and (Ia) wherein Ar, X, Y, and q have any of thevalues of the previous embodiments, and Z¹ is CR²¹═CR²¹, or C≡C. Otheraspects include compounds where Z¹ is C₆-C₁₀ arylene, or C₃-C₆cycloalkylene, particularly those where Z¹ is phenyl. Other aspectsinclude compounds where Z¹ is 5-10 membered heteroarylene, or 3-6membered heterocycloalkylene.

Further aspects of the present invention include compounds of formula(A) and formulas (I) and (Ia) wherein Ar, X and q have any of the valuesof the previous embodiments, and Y is (C₁-C₄ alkylene)_(m)—Z²—(C₁-C₄alkylene), wherein Z² is O, NR^(10A), or S(O)_(y). Other aspects includethose compounds where Y is C₁-C₄ alkylene-Z², wherein R¹ cannot be H.Other aspects include those compounds where Y is C₁-C₄ alkylene-Z²—C₁-C₄alkylene. Additional aspects include any of the above embodiments of Ywherein Z² is O. Additional aspects include any of the above embodimentsof Y wherein Z² is NR^(10A).

Further aspects of the present invention include compounds of formula(A) and formulas (I) and (Ia) wherein Ar, Y, Z¹, and Z², and q have anyof the values of the previous embodiments, and R¹ can be any valueselected from the following 12 enumerated paragraphs:

-   -   1. H.    -   2. NR¹²R¹³.    -   3. NR²¹C(═O)R¹⁴.    -   4. C(═O)R¹⁴.    -   5. CO₂R¹¹.    -   6. OC(═O)R¹¹.    -   7. C(═O)NR¹²R¹³.    -   8. C(═NR¹¹)NR¹²R¹³.    -   9. OC(═O)NR¹²R¹³.    -   10. NR²¹S(O)₂R¹¹.    -   11. NR²¹C(═O)NR¹²R¹³.    -   12. NR²¹S(O)₂NR¹²R¹³.

Other additional aspects of the present invention include compounds offormula (A) and formulas (I) and (Ia) wherein Ar, Y, Z¹, and Z², and qhave any of the values of the previous embodiments, and R¹ can be acombination of the values selected from the previous 12 enumeratedparagraphs. The preceding 12 enumerated paragraphs may be combined tofurther define additional preferred embodiments of compounds of thepresent invention. For example, one such combination includes NR¹²R¹³,NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, andNR²¹S(O)₂NR¹²R¹³.

Another such combination includes NR¹²R¹³, wherein R¹² and R¹³ are eachindependently selected from H and C₁-C₆ alkyl; NR²¹C(═O)R¹⁴;C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³; and NR²¹C(═O)NR¹²R¹³.

A third such combination includes C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,C(═O)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, and NR²¹S(O)₂NR¹²R¹³.

A fourth such combination includes NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,OC(═O)R¹¹, and C(═O)NR¹²R¹³.

A fifth such combination includes NR²¹C(═O)R¹⁴ and C(═O)NR¹²R¹³.

In still further aspects of the present invention, there are includedcompounds of formula (Ib):

wherein Ar, X and Y have any of the values of the previous embodiments.

Additional aspects of the present invention include compounds of formula(A) and formulas (I), (Ia) and (Ib) wherein Ar, X, Y, Z¹, Z², R¹, and qhave any of the values of the previous embodiments, and R¹² and R¹³ areeach independently selected from H and C₁-C₆ alkyl.

Other aspects of the present invention include compounds of formula (A)and formulas (I), (Ia) and (Ib) wherein Ar, Y, Z¹, Z², R¹, and q haveany of the values of the previous embodiments, and R¹² and R¹³ togetherwith the nitrogen to which they are attached, form a 3-7 memberedheterocyclic ring, particularly those where the heterocyclic ring is aheterocycloalkyl group, and more particularly those where theheterocyclic group is pyrrolidine or piperidine. In certain aspects, theheterocyclic ring is substituted with one R²⁰. In other aspects, theheterocyclic ring is unsubstituted.

Other aspects of the present invention include compounds of formula (A)and formulas (I), (Ia) and (Ib), wherein Y is C₁-C₆ alkylene and/or R¹is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³.

In accordance with a preferred embodiment, Ar is a C₆-C₁₀ aryl, morepreferably phenyl or naphtyl.

In accordance with another preferred embodiment, Ar is a 5-10 memberedheteroaryl, notably a 5 or 6 membered heteroaryl such as thienyl orfuryl.

Ar is optionally substituted with one to three groups, preferablyselected from halogen atoms (F, Cl, Br, I), OR²², or phenyl.

In that context, the following Ar substituents are particularlypreferred.

Preferably, halogen atoms are Cl and F.

Preferably, OR²² is O(C₁-C₆) alkyl such as O-methyl, O-ethyl,O-isopropyl.

In accordance with a preferred embodiment, X is O, S(O)_(y), N(R¹⁰),OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O),S(O)₂NR²², NR²²S(O)₂.

Preferably, X is O, S(O)_(y), NH, OCH₂, CH₂O, CH₂NH, NHCH₂, C(═O)NH,NHC(═O), S(O)₂NH, NHS(O)₂, more preferably O, S, SO, NH, OCH₂, CH₂NH,C(═O)NH, S(O)₂NH.

In accordance with a preferred embodiment Y is (C₁-C₆) alkylene,preferably unsubstituted (C₁-C₆) alkylene and more preferably CH₂.

In accordance with a preferred embodiment, R¹ is selected from H,CO₂R¹¹, C(═O)NR¹²R¹³, and is more preferably a C(═O)NR¹²R¹³.

Preferably, R¹² and R¹³, at each occurrence are each independentlyselected from H, C₁-C₆ alkyl, or R¹² and R¹³ together with the nitrogento which they are attached, form a 3-7 membered heterocyclic ring.

According to a preferred embodiment R¹² and R¹³ together with thenitrogen to which they are attached, form a 3-7 membered heterocyclicring, more preferably a 5-6 membered heterocyclic ring.

Preferably, the heterocyclic ring is a cycloalkyl group in which one ormore ring atoms, more preferably one or two, are replaced by —N—.

Preferably, the heterocyclic ring is selected from the group consistingof pyrrolidinyl, piperidyl and piperazinyl.

The heterocyclic ring may be substituted with one to three R²⁰ groups,preferably independently selected from C₁-C₆ alkyl optionallysubstituted with one to three OH, C(═O)R²², CO₂R²², C(═O)NR²³R²⁴.

Examples of R²⁰ representing a C(═O)R²² group are notably the groupswherein R²² represents a C₁-C₆ alkyl group such as acetyl (C(═O)CH₃), orethylcarbonyl (C(═O)CH₂CH₃).

Examples of R²⁰ representing a CO₂R²² group are notably CO₂R²² whereinR²² is H or C₁-C₆ alkyl such as ter-butoxycarbonyl (Boc) (CO₂(tBu)).

Examples of R²⁰ representing a C₁-C₆ alkyl group optionally substitutedwith one to three OH are notably hydroxyethyl.

In accordance with another preferred embodiment, R¹² and R¹³, at eachoccurrence are each independently selected from H or C₁-C₆ alkyl.

Examples of R¹², R¹³ representing a C₁-C₆ alkyl group are notablymethyl, ethyl, t-butyl, optionally substituted with one to three R²⁰groups, notably OH or CN.

Examples of C(═O)NR¹²R¹³ wherein R¹² and R¹³ are each independentlyselected from H or C₁-C₆ alkyl are notably C(═O)NH₂ or C(═O)NMe₂,C(═O)NH(CH₂)₂OH, C(═O)NHCMe₃.

In a prefered embodiment of the present invention there are providedcompounds of formula (A) and formula (I):

wherein Ar, X, R² and R³, q, Y—R¹ are defined in the Table 1 below.

In Table 1, the term “position” refers to the position of the Ar—Xlateral side chain as compared to —CH₂—S(O)q—Y—R¹ group on the centralbenzyl ring.

In addition, the positions of substituents on the Ar group and on thecentral core phenyl group are numbered as follows: TABLE 1

Ex. n° Ar X Position* R² R³ q Y—R¹  13 3,4-DiClPh O para H H 0 CH₂CO-N-piperazinyl-N-Boc  14 3,4-DiClPh O para H H 0 CH₂CO-N-piperazinyl  193,4-DiClPh O para H H 1 CH₂CO-N-piperazinyl  16 4-ClPh S para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  23 4-ClPh S para H H 1CH₂CO-1-(4-acetyl)- piperazinyl  24 4-ClPh SO para H H 1CH₂CO-1-(4-acetyl)- piperazinyl  29 Ph O para H H 1 CH₂CONHCHMe₂ Ph Ometa H H 0 CH₂CO-N- pyrrolidinyl  31 Ph O meta H H 1 CH₂CO-N-pyrrolidinyl Ph O meta H H 0 CH₂CONH₂  32 Ph O meta H H 1 CH₂CONH₂ Ph Ometa H H 0 CH₂CONMe₂  33 Ph O meta H H 1 CH₂CONMe₂ Ph O meta H H 0CH₂CONHCHMe₂  34 Ph O meta H H 1 CH₂CONHCHMe₂ Ph O meta H H 0CH₂CO-1-(4-acetyl)- piperazinyl  35 Ph O meta H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 4-OCH₃Ph O para H H 0 CH₂CONH₂  36 4-OCH₃Ph O para H H 1CH₂CONH₂ 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  374-OCH₃Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para HH 0 CH₂CO-N-piperazinyl  38 4-OCH₃Ph O para H H 1 CH₂CO-N-piperazinyl3,4-DiClPh O para H H 0 CH₂CONH₂  39 3,4-DiClPh O para H H 1 CH₂CONH₂ 11 3,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  223,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl  27 3,4-DiClPh Opara H H 2 CH₂CO-1-(4-acetyl)- piperazinyl  30 3,4-DiClPh O para H H 1CH₂COOH  15 3,4-DiClPh O ortho H H 0 CH₂CONH₂  20 3,4-DiClPh O ortho H H1 CH₂CONH₂ 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  403,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh Opara H H 0 CH₂CO-1-(4- carboxamide)- piperazinyl  41 3,4-DiClPh O para HH 1 CH₂CO-1-(4- carboxamide)- piperazinyl 4-OCH₃Ph O ortho H H 0CH₂CONH₂  42 4-OCH₃Ph O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0CH₂CONH₂  43 2-ClPh O para H H 1 CH₂CONH₂ 4-OHPh O ortho H H 0 CH₂CONH₂ 44 4-OHPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho H H 0 CH₂CONH₂  452-ClPh O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  46 2-ClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-ClPh O para H H 0 CH₂CO-N-piperazinyl  47 2-ClPh O para H H 1CH₂CO-N-piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 48 4-FPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl  95 4-FPh O paraH H 2 CH₂CO-1-(4-acetyl)- piperazinyl  96 4-FPh O para H H 1 CH₂COOH4-FPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  49 4-FPh O ortho HH 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-FPh O para H H 0 CH₂CONH₂  504-FPh O para H H 1 CH₂CONH₂ 4-FPh O ortho H H 0 CH₂CONH₂  51 4-FPh Oortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CONH₂  52 2-Naphthyl Oortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  53 2-Naphthyl O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-Naphthyl O para H H 0 CH₂CONH₂  54 2-Naphthyl O para H H 1 CH₂CONH₂2-BiPh O para H H 0 CH₂CONH₂  55 2-BiPh O para H H 1 CH₂CONH₂ 2-BiPh Oortho H H 0 CH₂CONH₂  56 2-BiPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho HH 0 CH₂CO-1-(4-acetyl)- piperazinyl  57 2-ClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2-Naphthyl O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  58 2-Naphthyl O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2-BiPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  59 2-BiPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-BiPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  60 2-BiPh O para HH 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-ClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  61 4-ClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para H H 0CH₂CO-1-(4-methyl)- piperazinyl  62 4-OCH₃Ph O para H H 1CH₂CO-1-(4-methyl)- piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-1-(4-ethylcarboxylate)- piperazinyl  63 3,4-DiClPh O para H H 1 CH₂CO-1-(4-ethylcarboxylate)- HHpiperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-hydroxyethyl)- piperazinyl  64 4-FPh O para H H 1 CH₂CO-1-(4-hydroxyethyl)- piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-hydroxyethyl)- piperazinyl  65 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4-hydroxyethyl)- piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-methyl)-piperazinyl  66 4-FPh O para H H 1 CH₂CO-1-(4-methyl)- piperazinyl4-ClPh O para H H 0 CH₂CONH₂  67 4-ClPh O para H H 1 CH₂CONH₂ 4-FPh Opara H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  68 4-FPh O para HH 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-OCH₃Ph O para H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  69 4-OCH₃Ph O para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-ClPh S para H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  70 4-ClPh S para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  71 4-ClPh SO para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 3,4-DiClPh O ortho H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  72 3,4-DiClPh O ortho H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl Ph O ortho H H 0 CH₂CONH₂  97Ph O ortho H H 1 CH₂CONH₂ Ph O ortho H H 0 CH₂CO-N- pyrrolidinyl  98 PhO ortho H H 1 CH₂CO-N- pyrrolidinyl Ph O ortho H H 0 CH₂CONMe₂  99 Ph Oortho H H 1 CH₂CONMe₂ Ph O para H H 0 CH₂CONMe₂ 100 Ph O para H H 1CH₂CONMe₂ Ph O para H H 0 CH₂CO-N- pyrrolidinyl 101 Ph O para H H 1CH₂CO-N- pyrrolidinyl Ph O para H H 0 CH₂CONH₂ 102 Ph O para H H 1CH₂CONH₂ Ph O ortho H H 0 CH₂CONHCH₂CN 103 Ph O ortho H H 1 CH₂CONHCH₂CNPh O ortho H H 0 CH₂CONHCHMe₂ 104 Ph O ortho H H 1 CH₂CONHCHMe₂ Ph Oortho H H 0 CH₂CONHCMe₃ 105 Ph O ortho H H 1 CH₂CONHCMe₃ Ph O ortho H H0 CH₂CO-1-(4- hydroxy)-piperidinyl 106 Ph O ortho H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl  12 Ph O ortho H H 0 CH₂CONH(CH₂)₂OH  21 Ph O orthoH H 1 CH₂CONH(CH₂)₂OH Ph O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl107 Ph O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl Ph O meta H H 0CH₂CONH(CH₂)₂OH 108 Ph O meta H H 1 CH₂CONH(CH₂)₂OH Ph O meta H H 0CH₂CO-1-(4- hydroxy)-piperidinyl 109 Ph O meta H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl 110 Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl111 Ph O para H H 1 CH₂CONH(CH₂)₂OH 112 Ph O para H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl 113 4-ClPh CONH ortho H H 1 CH₂CONH₂ 1143,4-DiOCH₃Ph CONH ortho H H 1 CH₂CONH₂ 115 2-Naphthyl CONH ortho H H 1CH₂CONH₂ 116 4-ClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 1173,4DiFPh CONH ortho H H 1 CH₂CONH₂ 118 2,4-DiOCH₃Ph CONH ortho H H 1CH₂CONH₂ 119 3,4,5- CONH ortho H H 1 CH₂CONH₂ TriOCH₃Ph 120 3,4-DiOCH₃PhCONH meta H H 1 CH₂CONH₂ 121 2,4-DiOCH₃Ph CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 122 3,4-DiOCH₃Ph CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 123 4-FPh CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 124 3,4-DiClPh CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 125 2,4-DiOCH₃Ph CONH meta H H 1CH₂CONH₂ 126 4-FPh CONH meta H H 1 CH₂CONH₂ 127 3,4-DiClPh CONH meta H H1 CH₂CONH₂ 7 4-ClPh O para H H 0 CH₃ 8 4-ClPh O para H H 1 CH₃ 9 4-ClPhO para H H 1 CH₂[4(4- ClPhenoxy)phenyl] 3,4-DiClPh O para H H 0 CH₃  103,4-DiClPh O para H H 1 CH₃ 4-ClPh S ortho H H 0 CH₂CO-N-piperazinyl  734-ClPh S ortho H H 1 CH₂CO-N-piperazinyl 2,3-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  74 2,3-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  75 2,5-DiCiPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0 CH₂CONH₂  762,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,3-DiClPh O ortho H H 0 CH₂CONH₂  772,3-DiClPh O ortho H H 1 CH₂CONH₂ 2,4-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  78 2,4-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  79 2,4-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O para H H 0 CH₂CONH₂  802,4-DiClPh O para H H 1 CH₂CONH₂ 2,4-DiClPh O ortho H H 0 CH₂CONH₂  812,4-DiClPh O ortho H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  82 3,5-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  83 3,5-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0 CH₂CONH₂  843,5-DiClPh O para H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0 CH₂CONH₂  853,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,5-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  86 2,5-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh S para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  87 3,4-DiClPh S para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh S para H H 0 CH₂CONH₂  882,5-DiClPh S para H H 1 CH₂CONH₂ 3,4-DiClPh S para H H 0 CH₂CONH₂  893,4-DiClPh S para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  90 2,3-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  91 2,6-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0 CH₂CONH₂  922,6-DiClPh O para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0 CH₂CONH₂  932,3-DiClPh O para H H 1 CH₂CONH₂  94 2,3-DiClPh O para H H 2 CH₂CONH₂135 Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 136 Ph NH para H H1 CH₂CO-1-(4-acetyl)- piperazinyl 134 4-OCH₃Ph NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 131 4-FPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 137 4-OCH₃Ph NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 138 4-FPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 139 4-ClPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 140 4-FPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 128 3,4-DiClPh CONH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 129 4-FPh CONH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 141 3,4-DiClPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 132 4-ClPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 147 4-FPh CH₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 133 3,4-DiClPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 148 3,4-DiClPh CH₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 149 4-FPh CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 146 3,4-DiClPh CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 130 3,4-DiClPh SO₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 145 2-Furyl CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 144 2-Thienyl CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 142 2-Thienyl CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 143 2-Furyl CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 152 Ph OCH₂ ortho H H 0 CH₂CONH₂ 153 PhOCH₂ ortho H H 1 CH₂CONH₂  17 4-ClPh O para 2′-Cl H 0CH₂CO-1-(4-acetyl)- piperazinyl  18 4-ClPh O para 2′-Cl H 0 CH₂CONH₂  254-ClPh O para 2′-Cl H 1 CH₂CO-1-(4-acetyl)- piperazinyl  26 4-ClPh Opara 2′-Cl H 1 CH₂CONH₂ 149a 3,4-DiClPh CONH para H H 1 CH₂CONH₂ 109a4-ClPh O ortho H H 1 CH₂CONH₂ 109b 3-Cl-4-FPh O ortho H H 1 CH₂CONH₂109c 4-Cl-3-FPh O ortho H H 1 CH₂CONH₂ 109d 3-Cl-4-FPh O ortho H H 2CH₂CONH₂  10a 4-ClPh O ortho 4′-Cl H 0 CH₂COOH  18a 4-ClPh O ortho 4′-ClH 0 CH₂CONH₂  27a 4-ClPh O ortho 4′-Cl H 1 CH₂CONH₂  27b 4-ClPh O ortho4′-Cl H 2 CH₂CONH₂ 109e 3,4-DiFPh O ortho 4′-Cl H 1 CH₂CONH₂ 109f3,4-DiClPh O ortho H H 2 CH₂CONH₂  30a 3,4-DiClPh O ortho H H 1 CH₂COOH 30d 3,4-DiClPh O ortho H H 0 CH₂COOMenthyl (1R,2S,5R)  30e 3,4-DiClPh Oortho H H 1 CH₂CO0H (−)  30f 3,4-DiClPh O ortho H H 1 CH₂COOH (+)  20a3,4-DiClPh O ortho H H 1 CH₂CONH₂ (−)  20b 3,4-DiClPh O ortho H H 1CH₂CONH₂ (+)  30b 3,4-DiClPh O ortho H H 2 CH₂COOH 112a 3,4-DiClPh Oortho H H 1 CH₂CONHCH₃ 112b 3,4-DiClPh O ortho H H 1 CH₂CON(C₂H₅)₂  30f3,4-DiClPh O ortho H H 0 CH₂CON(CH₃)₂  30g 3,4-DiClPh O ortho H H 1CH₂CON(CH₃)₂Ph = phenyl, ClPh = chlorophenyl, DiClPh = di-chlorophenyl, FPh =Fluoprophenyl.*Position: Ortho is position 2′, meta is position 3′ and para isposition 4′.

In a second embodiment, the present invention provides a method fortreatment of diseases comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula (A)and formula (I), or a pharmaceutically acceptable salt thereof. In apreferred embodiment, the present invention is to provide methods oftreating or preventing diseases or disorders, including treatment ofsleepiness, promotion and/or improvement of wakefulness, preferablyimprovement of wakefulness in patients with excessive sleepinessassociated with narcolepsy, sleep apnea, preferably obstructive sleepapnea/hypopnea, and shift work disorder; treatment of Parkinson'sdisease; Alzheimer's disease; cerebral ischemia; stroke; eatingdisorders; attention deficit disorder (“ADD”), attention deficithyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue,preferably fatigue associated with cancer or neurological diseases, suchas multiple sclerosis and chronic fatigue syndrome; stimulation ofappetite and weight gain and improvement of cognitive dysfunction.

In a third embodiment, the present invention provides a pharmaceuticalcompositions comprising the compounds of formula (A) and formula (I)wherein the compositions comprise one or more pharmaceuticallyacceptable excipients and a therapeutically effective amount of at leastone of the compounds of the present invention, or a pharmaceuticallyacceptable salt or ester form thereof.

In a fourth embodiment, the present invention provides for the use ofcompounds of formula (A) and formula (I) or pharmaceutically acceptablesalts thereof for the manufacture of a medicament for the treatment of adisease or disorder.

These and other objects, features and advantages of the benzyl-thioalkylderivatives will be disclosed in the following detailed description ofthe patent disclosure.

Definitions

The following terms and expressions contained herein are defined asfollows:

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50 mg” includes±10% of 50, or from 45 to 55 mg.

As used herein, a range of values in the form “x-y” or “x to y”, or “xthrough y”, include integers x, y, and the integers therebetween. Forexample, the phrases “1-6”, or “1 to 6” or “1 through 6” are intended toinclude the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments includeeach individual integer in the range, as well as any subcombination ofintegers. For example, preferred integers for “1-6” can include 1, 2, 3,4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, etc.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

As used herein, the term “alkyl” refers to a straight-chain, or branchedalkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl moiety ofalkyl-containing groups, such as alkoxy, alkoxycarbonyl, andalkylaminocarbonyl groups, has the same meaning as alkyl defined above.Lower alkyl groups, which are preferred, are alkyl groups as definedabove which contain 1 to 4 carbons. A designation such as “C₁-C₄ alkyl”refers to an alkyl radical containing from 1 to 4 carbon atoms.

As used herein, the term “alkenyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon double bond. A designation “C₂-C₈ alkenyl” refers to analkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenylgroups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc.

As used herein, the term “alkynyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon triple bond. A designation “C₂-C₈ alkynyl” refers to analkynyl radical containing from 2 to 8 carbon atoms. Examples includeethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc.

As used herein, the term “alkylene” refers to a substituted orunsubstituted, branched or straight chained hydrocarbon of 1 to 8 carbonatoms, which is formed by the removal of two hydrogen atoms. Adesignation such as “C₁-C₄ alkylene” refers to an alkylene radicalcontaining from 1 to 4 carbon atoms. Examples include methylene (—CH₂—),propylidene (CH₃CH₂CH═), 1,2-ethandiyl (—CH₂CH₂—), etc.

As used herein, the term “phenylene” refers to a phenyl group with anadditional hydrogen atom removed, i.e. a moiety with the structure of:

As used herein, the terms “carbocycle”, “carbocyclic” or “carbocyclyl”refer to a substituted or unsubstituted, stable monocyclic or bicyclichydrocarbon ring system which is saturated, partially saturated orunsaturated, and contains from 3 to 10 ring carbon atoms. Accordinglythe carbocyclic group may be aromatic or non-aromatic, and includes thecycloalkyl and aryl compounds defined herein. The bonds connecting theendocyclic carbon atoms of a carbocyclic group may be single, double,triple, or part of a fused aromatic moiety.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated mono- or bicyclic alkyl ring system containing 3 to 10 carbonatoms. A designation such as “C₅-C₇ cycloalkyl” refers to a cycloalkylradical containing from 5 to 7 ring carbon atoms. Preferred cycloalkylgroups include those containing 5 or 6 ring carbon atoms. Examples ofcycloalkyl groups include such groups as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexl, cycloheptyl, cyclooctyl, pinenyl, andadamantanyl.

As used herein, the term “aryl” refers to a substituted orunsubstituted, mono- or bicyclic hydrocarbon aromatic ring system having6 to 12 ring carbon atoms. Examples include phenyl and naphthyl.Preferred aryl groups include unsubstituted or substituted phenyl andnaphthyl groups. Included within the definition of “aryl” are fused ringsystems, including, for example, ring systems in which an aromatic ringis fused to a cycloalkyl ring. Examples of such fused ring systemsinclude, for example, indane, indene, and tetrahydronaphthalene.

As used herein, the terms “heterocycle”, “heterocyclic” or“heterocyclyl” refer to a substituted or unsubstituted carbocyclic groupin which the ring portion includes at least one heteroatom such as O, N,or S. The nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen may be optionally substituted in non-aromatic rings.Heterocycles are intended to include heteroaryl and heterocycloalkylgroups.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as —O—, —N—, or —S—. Examples of heterocycloalkylgroups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pirazolidinyl, pirazolinyl, pyrazalinyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dithiolyl, oxathiolyl,dioxazolyl, oxathiazolyl, pyranyl, oxazinyl, oxathiazinyl, andoxadiazinyl.

As used herein, the term “heteroaryl” refers to an aromatic groupcontaining 5 to 10 ring carbon atoms in which one or more ring carbonatoms are replaced by at least one hetero atom such as —O—, —N—, or —S—.Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl,pirazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl,oxathiolyl, oxadiazolyl, triazolyl, oxatriazolyl, furazanyl, tetrazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl,isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, purinyl,quinazolinyl, quinolyl, isoquinolyl, benzoimidazolyl, benzothiazolyl,benzothiophenyl, thianaphthenyl, benzoxazolyl, benzisoxazolyl,cinnolinyl, phthalazinyl, naphthyridinyl, and quinoxalinyl. Includedwithin the definition of “heteroaryl” are fused ring systems, including,for example, ring systems in which an aromatic ring is fused to aheterocycloalkyl ring. Examples of such fused ring systems include, forexample, phthalamide, phthalic anhydride, indoline, isoindoline,tetrahydroisoquinoline, chroman, isochroman, chromene, and isochromene.

As used herein, the term “arylalkyl” refers to an alkyl group that issubstituted with an aryl group. Examples of arylalkyl groups include,but are not limited to, benzyl, bromobenzyl, phenethyl, benzhydryl,diphenylmethyl, triphenylmethyl, diphenylethyl, naphthylmethyl, etc.

As used herein, the term “amino acid” refers to a group containing bothan amino group and a carboxyl group. Embodiments of amino acids includeα-amino, β-amino, γ-amino acids. The α-amino acids have a generalformula HOOC—CH(side chain)-NH₂. In certain embodiments, substituentgroups for the compounds of the present invention include the residue ofan amino acid after removal of the hydroxyl moiety of the carboxyl groupthereof; i.e., groups of formula —C(═O)CH(NH₂)-(side chain). The aminoacids can be in their D, L or racemic configurations. Amino acidsinclude naturally-occurring and non-naturally occurring moieties. Thenaturally-occurring amino acids include the standard 20 α-amino acidsfound in proteins, such as glycine, serine, tyrosine, proline,histidine, glutamine, etc. Naturally-occurring amino acids can alsoinclude non-α-amino acids (such as β-alanine, γ-aminobutyric acid,homocysteine, etc.), rare amino acids (such as 4-hydroxyproline,5-hydroxylysine, 3-methylhistidine, etc.) and non-protein amino acids(such as citrulline, ornithine, canavanine, etc.). Non-naturallyoccurring amino acids are well-known in the art, and include analogs ofnatural amino acids. See Lehninger, A. L. Biochemistry, 2^(nd) ed.;Worth Publishers: New York, 1975; 71-77, the disclosure of which isincorporated herein by reference. Non-naturally occurring amino acidsalso include α-amino acids wherein the side chains are replaced withsynthetic derivatives. Representative side chains of naturally occurringand non-naturally occurring a-amino acids are shown below in Table 2.TABLE 2 H CH₃ CH(CH₃)₂ CH₂CH(CH₃)₂ CH(CH₃)CH₂CH₃ CH₂OH CH₂SH CH(OH)CH₃CH₂CH₂SCH₃ CH₂C₆H₅ (CH₂)₄NH₂ (CH₂)₃NHC(═NH)NH₂ CH₂COOH CH₂CH₂COOHCH₂CONH₂ CH₂CH₂CONH₂ CH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₂CH₃ CH₂CH₂SH CH₂CH₂OHCH₂CH₂SCH₃ (CH₂)₃NH₂ (CH₂)₂CH(OH)CH₂NH₂ (CH₂)₃NHC(═O)NH₂(CH₂)₂ONHC(═NH)NH₂ CH₂C(═O)NHCH₂COOH

As used herein, the term “subject” refers to a warm blooded animal suchas a mammal, preferably a human, or a human child, which is afflictedwith, or has the potential to be afflicted with one or more diseases andconditions described herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention effective to prevent or treat thesymptoms of particular disorder. Such disorders include, but are notlimited to, those pathological and neurological disorders associatedwith the aberrant activity of the receptors described herein, whereinthe treatment or prevention comprises inhibiting, inducing, or enhancingthe activity thereof by contacting the receptor with a compound of thepresent invention.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter.

All other terms used in the description of the present invention havetheir meanings as is well known in the art.

In another aspect, the present invention is directed to pharmaceuticallyacceptable salts of the compounds described above. As used herein,“pharmaceutically acceptable salts” includes salts of compounds of thepresent invention derived from the combination of such compounds withnon-toxic acid or base addition salts.

Acid addition salts include inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as wellas organic acids such as acetic, citric, propionic, tartaric, glutamic,salicylic, oxalic, methanesulfonic, para-toluenesulfonic, succinic, andbenzoic acid, and related inorganic and organic acids.

Base addition salts include those derived from inorganic bases such asammonium and alkali and alkaline earth metal hydroxides, carbonates,bicarbonates, and the like, as well as salts derived from basic organicamines such as aliphatic and aromatic amines, aliphatic diamines,hydroxy alkamines, and the like. Such bases useful in preparing thesalts of this invention thus include ammonium hydroxide, potassiumcarbonate, sodium bicarbonate, calcium hydroxide, methylamine,diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and thelike.

In addition to pharmaceutically-acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of the compounds, in the preparation of other salts, or inthe identification and characterization of the compounds orintermediates.

The pharmaceutically acceptable salts of compounds of the presentinvention can also exist as various solvates, such as with water,methanol, ethanol, dimethylformamide, ethyl acetate and the like.Mixtures of such solvates can also be prepared. The source of suchsolvate can be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent. Such solvates are within the scope of the present invention.

The present invention also encompasses the pharmaceutically acceptableprodrugs of the compounds disclosed herein. As used herein, “prodrug” isintended to include any compounds which are converted by metabolicprocesses within the body of a subject to an active agent that has aformula within the scope of the present invention. Since prodrugs areknown to enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds of thepresent invention may be delivered in prodrug form. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Prodrugs, Sloane, K. B., Ed.;Marcel Dekker: New York, 1992, incorporated by reference herein in itsentirety.

It is recognized that compounds of the present invention may exist invarious stereoisomeric forms. As such, the compounds of the presentinvention include both diastereomers and enantiomers. The compounds arenormally prepared as racemates and can conveniently be used as such, butindividual enantiomers can be isolated or synthesized by conventionaltechniques if so desired. Such racemates and individual enantiomers andmixtures thereof form part of the present invention.

It is well known in the art how to prepare and isolate such opticallyactive forms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,and chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J., et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compoundsof Formula I may contain protecting groups. For example, the amino acidside chain substituents of the compounds of Formula I can be substitutedwith protecting groups such as benzyloxycarbonyl or t-butoxycarbonylgroups. Protecting groups are known per se as chemical functional groupsthat can be selectively appended to and removed from functionalities,such as hydroxyl groups and carboxyl groups. These groups are present ina chemical compound to render such functionality inert to chemicalreaction conditions to which the compound is exposed. Any of a varietyof protecting groups may be employed with the present invention.Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) groupand the tert-butyloxycarbonyl (Boc) group. Other preferred protectinggroups according to the invention may be found in Greene, T. W. andWuts, P. G. M., “Protective Groups in Organic Synthesis” 2d. Ed., Wiley& Sons, 1991.

Synthesis

The compounds of the present invention may be prepared in a number ofmethods well known to those skilled in the art, including, but notlimited to those described below, or through modifications of thesemethods by applying standard techniques known to those skilled in theart of organic synthesis. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare such optically active forms. For example, mixtures ofstereoisomers may be separated by standard techniques including, but notlimited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from active startingmaterials or by deliberate chiral synthesis of target centers.

As will be readily understood, functional groups present on thecompounds of Formula I may contain protecting groups. For example, theamino acid side chain substituents of the compounds of Formula I can besubstituted with protecting groups such as benzyloxycarbonyl ort-butoxycarbonyl groups. Protecting groups are known per se as chemicalfunctional groups that can be selectively appended to and removed fromfunctionalities, such as hydroxyl groups and carboxyl groups. Thesegroups are present in a chemical compound to render such functionalityinert to chemical reaction conditions to which the compound is exposed.Any of a variety of protecting groups may be employed with the presentinvention. Preferred protecting groups include the benzyloxycarbonyl(Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Otherpreferred protecting groups according to the invention may be found inGreene, T. W. and Wuts, P. G. M., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991.

The general routes to prepare the examples shown in Table 1 of thepresent invention are shown in the Scheme A, Scheme B, Scheme C andScheme D. The reagents and starting materials are commerciallyavailable, or readily synthesized by well-known techniques by one ofordinary skill in the arts. All substituents in the synthetic Schemes,unless otherwise indicated, are as previously defined.

Compounds of general structure (A) and/or (I) were prepared according toScheme A.

Step 1: Synthesis of Compounds of General Structure C:

An appropriate aromatic or heteroaromatic alcohol or thiol of generalformula A is reacted with an appropriate halo-aryl or halo-heteroarylaldehyde or acid of general formula B, in a polar aprotic solvent as DMFand like at reflux temperature to give the corresponding aldehyde oracid compound C wherein Ar, X, R² and R³ are as defined in the finalproduct and W represents the acid or the aldehyde group. An appropriatearomatic or heteroaromatic alcohol or thiol of general formula A is onewhere Ar is as defined in the final product and X represents oxygen orsulfure atoms. An appropriate halo-aryl or halo-heteroaryl aromaticaldehyde or acid of general formula B is one where R² and R³ are asdefined in the final product, W is an acid or an aldehyde group and halis an halogen atom: F, Cl, Br. Upon completion, the reaction mixture isquenched by an appropriate quenching agent and the product, compound C,is isolated by conventional methods commonly employed by those skilledin the art. Compounds of general formula C may also be commerciallyavailable.

Step 2: Synthesis of Compounds of General Structure D:

The appropriate compound C of the preceding step, dissolved in a proticpolar solvent as isopropanol and like, may be treated with a suitablereducing agent such as metallic hydrides. For example, the compound Cmay be treated with sodium borohydride (or other standard reductiveconditions as LiAlH4, diisobutylaluminium hydride and like) in order toprovide the corresponding alcohol of general formula D. When thestarting material is a compound C bearing an acidic function (W isCOOH), the reduction reaction might be performed after activation of thecarboxy moiety with an activating agent as isobutylchloroformate andlike, or by conventional methods commonly employed by those skilled inthe art.

Step 3: Synthesis of Compounds of General Structure E:

In step 3, the alcohol moiety of compound D is converted to thecorresponding thiouronium salt.

In a particular embodiment, the compound E is formed by reacting thecompound D with a suitable acid. In certain aspects, the suitable acidis selected from the group consisting of hydrobromic acid, hydrochloricacid or sulfuric acid.

For example, an appropriate amount of thiourea in 48% HBr and water iswarmed (preferably to 60-70° C.), followed by addition of compound D.The reaction mixture is refluxed and the stirring is continued for anadditional period of time for completion of the reaction. The reactionmixture is cooled to room temperature (in some cases, an ice-bath mightbe needed) and the precipitated solid is optionally filtered andthoroughly washed with water to generate compound E. Sometimes there isan oil in place of the solid: in that case, the oil is thoroughly washedwith water by decantation and used directly in step 4.

Step 4: Synthesis of Compounds of General Structure I Wherein q=0

The thiouronium salt of general structure E is first converted into thecorresponding thiol which further undergoes a substitution reaction withan appropriate reactant of generic structure LG-Y—R¹ wherein Y is asdefined in the final product and LG is a suitable leaving group (forexample an halogen atom as Cl, Br) to generate compound I wherein q is0.

In step 4, the wet solid (or the oil with some remaining water) from theprevious step is taken into additional water and treated with an aqueousbase, preferably sodium hydroxide solution. The mixture is warmedpreferably to 70-80° C., but in some cases a higher temperature might beneeded and to it an appropriate amount of LG-Y—R¹ in water (or in somecases, an alcoholic solvent) is added. The reaction mixture is refluxedfor an appropriate period of time, cooled, taken into water andsometimes washed with an organic solvent (preferably ether). The basicaqueous layer is acidified with an inorganic acid solution (e.g. aqueousHCl solution). The aqueous (acidic) solution is then extracted severaltimes into an organic solvent (e.g. ether or ethyl acetate). Thecombined organic layer is washed with brine, dried (MgSO₄ or Na₂SO₄) andconcentrated to give the crude product that may be used directly in thenext step. However, purification could be achieved by employing knownpurification techniques (e.g. recrystallization or columnchromatography) to provide pure compound I wherein q is O, Ar, X, R¹, Y,R² and R³ are as defined in the final product.

In addition, at Step 4, when the obtained compound I is an acid (R¹ isCOOH), appropriately, it may be converted into the corresponding alkylester by conventional methods commonly employed by those skilled in theart.

Step 5: Synthesis of Compounds of General Structure I Wherein q is 1 or2:

Compounds of structure I wherein q is 0 may optionally be oxidized togenerate compounds of structure I wherein q is 1 or 2. Compound Iwherein q is 1 is prepared under mild conditions by reacting compound Iwherein q is 0 in an appropriate solvent with an appropriate oxidizingagent. An appropriate oxidizing agent is one that oxidizes the sulphidegroup of compound I (wherein q is 0). The corresponding product isisolated and purified by methods well known in the art.

For example, to solution of compound I (wherein q is 0) in acetic acid,an appropriate oxidizing agent (e.g. 30% wt H₂O₂, 1 equivalent) in theacetic acid is slowly added. Stirring is continued at low temperatureuntil the disappearance of the starting material, as evidenced byvarious analytical techniques. The reaction mixture is concentrated. Thedesired product (compound I wherein q is 1) is purified, if needed, byemploying known purification techniques (preferably by columnchromatography and/or crystallization). In some cases, the oxidation isperformed by employing 50% H₂O₂ in glacial acetic acid solvent.

Compound of formula I wherein q is 2, may be obtained from theappropriate compound of formula I wherein q is either 0 or 1 under moredrastic reaction conditions such as H₂O₂ (more than 2 equivalents) inacidic medium, under heating, at temperature comprise between roomtemperature and the boiling temperature of the solvent, preferablybetween 40 and 60° C., for a time sufficient to obtain the desiredproduct, approximately between 2 and 10 hours, preferably approximately8 hours.

The following scheme (Scheme B) corresponds to the synthesis ofcompounds of general structure I wherein R¹ is C(═O)NR¹²R¹³.

The different steps 1, 2, 3 and 4 were as described in scheme A.

In addition, at Step 4, when the obtained compound I is an acid (R isH), appropriately, it may be converted into the corresponding alkylester by conventional methods commonly employed by those skilled in theart.

Then, two different synthetic routes may optionally be used to generatecompounds I wherein R¹ is C(═O)NR¹²R¹³.

Route A

Step 5: Synthesis of Compounds of General Formula I Wherein q is 0:

In step 5, the appropriate carboxylic acid or ester of general formula I(wherein q is 0) is reacted with an appropriate amine of generalstructure NHR¹²R¹³ and converted into the corresponding amide of generalformula I wherein q is 0 and Ar, X, R², R³, Y, R¹² and R¹³ are asdefined in the final product.

Compound I (wherein q is 0 and R1 is COOMe) may be reacted with Ammoniumhydroxide (28% aqueous solution as example) or ammonia gas to give thedesired compound I (wherein q is 0 and R¹² and R¹³ are H).Alternatively, compound I (wherein q is 0 and R1 is COOH) may be reactedwith an appropriate amine of general formula NHR¹²R¹³, a couplingreagent such as EDCI or DCCI, or a polymer supported coupling reagent(N-cyclohexyl carbodiimide), and optionally HOBT in an aprotic solventas methylene chloride and like to provide amide of general formula Iwherein q is 0. An appropriate amine is one which correlates to R¹² andR¹³ as defined in the final product. In some cases, when the appropriateamide bears a protecting group as the tert-butyloxycarbonyl (“Boc”) andlike on a second nitrogen group, N-boc amine is de-protected in asubsequent step. De-protection may be performed at room temperature byacid treatment such as 4N HCl in 1,4-dioxane or trifluoroacetic acid inCH₂Cl₂.

Step 6: Synthesis of Compounds of General Structure I Wherein q is 1 or2:

Compounds of structure I wherein q is 0 may optionally be oxidized togenerate compounds of structure I wherein q is 1 or 2 according to theprocedure described previously in Scheme A (step 5).

Route B

Route B may alternatively be used to process appropriately compound Iwherein R¹ is C(═O)NR¹²R¹³.

In step 5, the process consisted, in oxidizing an appropriate compound Iwherein q is 0 to generate the corresponding sufoxide or sulfone asdescribed above in step 6, which, in turn, is reacted with anappropriate amine of general formula NHR¹²R¹³, in the next step, to giveraise to the corresponding amide (compound I wherein q is 1 or 2) asdescribed above in step 5.Scheme C, corresponds to an alternative pathway to generate compounds ofgeneral structure I wherein X is different from O or S.

Step 1: Synthesis of Compounds of General Structure J:

An appropriate aromatic or heteroaromatic halide of general formula Hsubstituted with a nitro group in a suitable position as defined in thefinal product is reacted with an appropriate thiol-substitutedalkylcarboxylic acid or ester of structure HS-Y-R¹ (wherein R¹ is H oralkyl, and Y is defined as in the final compound) in an aprotic solventsuch as acetone and like and in the presence of an inorganic base aspotassium carbonate and a catalyst as potassium iodine and like togenerate compound J. The reaction is performed at reflux temperature.

Step 2: Synthesis of Compounds of General Structure M:

Route A

i) Oxidation Reaction: Synthesis of Compound of General Formula L

Then, appropriate compounds of general formula J wherein R¹, R² and R³and Y are as defined in the final product are prepared by reactingcompound J in an appropriate solvent with an appropriate oxidizingagent. An appropriate oxidizing agent is one that oxidizes the sulfidegroup of compound J. The corresponding product is isolated and purifiedby methods well known in the art.

For example, to solution of compound J in acetic acid, an appropriateoxidizing agent (e.g. 30% bw H₂O₂, 1 equivalent) in the same solvent isslowly added. Stirring is continued until the disappearance of thestarting material, as evidenced by various analytical techniques. Thereaction mixture is concentrated. The desired product (compound Lwherein q is 1) is purified, if needed, by employing known purificationtechniques (preferably by column chromatography and/or crystallization).In some cases, the oxidation is performed by employing 50% H₂O₂ inglacial acetic acid solvent.

Compound of formula L wherein q is 2, may be obtained under more drasticreaction conditions such as H₂O₂ (more than 2 equivalents) in acidicmedium, under heating, preferably at temperature comprise between roomtemperature and the boiling temperature of the solvent, preferablybetween 40 and 60° C., for a time sufficient to obtain the desiredproduct, usually approximately between 2 and 10 hours, preferablyapproximately 8 hours.

ii) Catalytic Hydrogenation

Appropriate amino compound of general formula M may be produced bycatalytic hydrogenation from the appropriate nitro compound of formulaL. The hydrogenation reaction is performed under pressure in a hydrogenatmosphere and catalytic conditions using a catalyst as palladium oncarbon or platinium oxide and like in an alcoholic solvent such asmethanol and like.

Route B

i) Synthesis of Compound of General Formula K

Before undergoing oxidation reaction, appropriately, compound J whereinR¹ is a carboxylic acid may be reacted with an appropriate amine ofstructure NHR¹²R¹³. The amidation reaction is performed using a couplingsuch as EDCI or DCCI, or a polymer supported coupling reagent(N-cyclohexyl carbodiimide) and optionally HOBT in an aprotic solvent asmethylene chloride and like to give the desired amide of general formulaK.

Alternatively, compound J wherein R¹ is a carboxylic acid may beconverted into the corresponding alkyl ester by conventional methodscommonly employed by those skilled in the art. Then, the ester isreacted with an appropriate amine of general structure NHR¹²R¹³ in thepresence of trimethyl aluminium hydride for instance or with ammoniumhydroxide (28% aqueous solution as example) or ammonia gas to give thedesired compound K.

ii) Oxidation and Catalytic Hydrogenation of Compound K

Compounds K wherein R¹ is an amide are then oxidized according to theprocess described above for Route A to generate the correspondingcompound of formula L which, in turn, is reduced in compound M accordingto the process described above in Route A.

Route C

The compound of general formula K wherein R¹ is the appropriate amideC(═O)NHR¹²R¹³, R² and R³ and Y are as defined in the final productprepared by amidation of compound J is reduced in compound M′ accordingto the process described above in route A. Then the correspondingcompound M wherein q is 1 or 2 is generated as according to theoxidation process described in Route A.

Step 3: Synthesis of Compounds of General Structure I Wherein X is NH,C(R²²)₂NH, C(═O)NH, S(O)₂NH.

Compounds of general formula I, wherein Ar, X, q, R², R³, Y and R¹ areas defined in the final product may be prepared in a one step procedurein suitable experimental conditions as to obtain the target Xdefinition.

For exemple, compound of formula I wherein X is NH may be obtained bycoupling an appropriate amine M with an appropriate boronic acid in anaprotic solvent as dichloromethane and the like. The reaction is carriedout in the presence of a base such as 2,6-lutidine and like as pyridine,triethylamine, diisopropylethylamine and in catalytic conditions usingcopper(II) acetate. An appropriate boronic acid is one which correlatesto Ar as defined in the final product.

Compounds of general formula I, wherein X is C(R²²)₂NH may be preparedin a one step procedure by alkylation an appropriate amine M with asuitable alkylating agent in an aprotic solvent as DMF, dichloromethaneand the like. A suitable alkylating agent is one which correlates to Arand R²² as defined in the final product.

Compounds of formula I wherein X is an amide may be obtained byaroylation of an appropriate amine M with an appropriate aromatic orheteroaromatic halide in an aprotic solvent as dichloromethane and thelike. The reaction is carried out in the presence of a base such as aspyridine, and the like triethylamine, diisopropylethylamine. Anappropriate aromatic or heteroaromatic halide is one which correlates toAr as defined in the final product.

Compounds of general formula I, wherein X is S(O)₂NH may be prepared ina one step procedure by sulfonation of an appropriate amine M with anappropriate aromatic or heteroaromatic sulfonyl chloride in an aproticsolvent. The reaction is carried out in the presence of a base such aspyridine, and like triethylamine, diisopropylethylamine. An appropriatearomatic or heteroaromatic sulfonyl chloride is one which correlates toAr as defined in the final product.

Compounds of general structure I were also generated according to SchemeD.

Scheme D, Synthesis of Compounds of General Structure I

Step 1: Synthesis of Compounds of General Structure O

An appropriate xylene of general formula N bearing two leaving groups ina suitable position as defined in the final product is reacted withappropriate thiol of structure HS—Y—R¹ wherein Y and R1 are as definedin the final product to generate compound of general formula O. Thereaction is carried out in an aprotic solvent such as DMF and like andin the presence of an inorganic base as potassium carbonate and at roomtemperature in an argon atmosphere.

Step 2: Synthesis of Compounds of General Structure I wherein q is 0:

Then compound O is reacted with an appropriate aryl or heteroarylalcohol, amine or thiol to generate compound of general formula Iwherein q is 1 and Ar, X, R¹, R² and R³ are as defined in the finalproduct.

In addition, when R¹ is an ester function, compound I may be hydrolysedat solvent reflux temperature and in the presence of an inorganic basebefore the amidification step.

Step one and step 2 may be processed without isolation of theintermediate O (one pot procedure).

Step 3: Synthesis of Compounds of General Structure I wherein q is 1 or2

i) Oxidation Reaction

Then, appropriate compounds of general formula I wherein R¹, R², R³, X,q and Y are as defined in the final product are prepared by reactingcompound I in an appropriate solvent with an appropriate oxidizingagent. An appropriate oxidizing agent is one that oxidizes the sulfidegroup of compound I. The corresponding product is isolated and purifiedby methods well known in the art.

For example, to solution of compound I in acetic acid, an appropriateoxidizing agent (e.g. 30% wt H₂O₂, 1 equivalent) in the same solvent isslowly added. Stirring is continued until the disappearance of thestarting material, as evidenced by various analytical techniques. Thereaction mixture is concentrated. The desired product (compound Iwherein q is 1) is purified, if needed, by employing known purificationtechniques (preferably by column chromatography and/or crystallization).In some cases, the oxidation is performed by employing 50% H₂O₂ inglacial acetic acid solvent.

Compound of formula I wherein q is 2, may be obtained under more drasticreaction conditions such as H₂O₂ (more than 2 equivalents) in acidicmedium, under heating, preferably at temperature comprise between roomtemperature and the boiling temperature of the solvent, preferablybetween 40 and 60° C., for a time sufficient to obtain the desiredproduct, usually approximately between 2 and 10 hours, preferablyapproximately 8 hours.

ii) Synthesis of Compound of General Formula I Wherein R¹ isC(═O)NHR¹²R¹³

Before undergoing oxidation reaction, appropriately, compound I whereinq is 0 and R¹ is an ester or an acid function may be reacted with anappropriate amine of structure NHR¹²R¹³. as already described in schemaB, route A.

Compounds I wherein R¹ is an amide are then oxidized according to theprocesses described above to generate the corresponding compound offormula I wherein q is 1 or 2.

EXAMPLES

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments. These examples aregiven for illustration of the invention and are not intended to belimiting thereof.

I—Compounds Prepared According to Schemes A and B.

The following Examples 1 to 112 were synthesized according to Schemes Aand B.

A—Preparation of Compounds C

Compound 1

Compound C wherein Ar is 3,4-DiClPhenyl, X is O, substitution in paraposition, W is C(═O)H.

To a stirred solution of A (aldehyde wherein Ar is 3,4-DiClPhenyl, X isO, 39 g, 239 mmol) in DMF (200 mL), parafluorobenzaldehyde (compound B;26 mL; 242 mmol) and cesium carbonate (80 g; 250 mmol) were added. Themixture was refluxed for 3 hours and then cooled to room temperature.After dilution with brine (800 mL), the resulting precipitate wasextracted with Et₂O (4×250 mL). The organic layer was washed with brine(3×300 mL), water (2×300 mL), and then dried over MgSO₄ and concentratedin vacuo. Trituration of the resulting residue with cold Et₂O,filtration and drying under vacuum gave 42 g (157 mmol) of compound 1 asan off-white solid.

Yield=66%.

R_(f)=0.94 (95:5 methylenechloride/methanol).

According to the procedure as described for compound 1, the followingcompounds were prepared.

Compound 2

Compound C wherein Ar is 3,4-DiClPhenyl, X is O, substitution in orthoposition, W is C(═O)H.

Reagents: compound A (wherein Ar is 3,4-DiClPhenyl, X is O, 39 g, 239mmol) and orthofluorobenzaldehyde (compound B; 26 mL; 242 mmol).

Yield=35% (22.3 g; 83 mmol of compound 2).

R_(f)=0.73 (eluent: 8:2 cyclohexane/ethylacetate).

Compound 3

Compound C wherein Ar is 4-ClPhenyl, X is S, substitution in paraposition, W is C(═O)H.

Reagents: compound A (wherein Ar is 4-ClPhenyl, X is S, 26.3 g, 182mmol) and parafluorobenzaldehyde (compound B; 20 mL; 242 mmol).

Yield=88% (40 g; 160 mmol of compound 3 as a yellow powder).

R_(f)=0.57 (eluent: 8:2 cyclohexane/ethylacetate).

Compound 4

Compound C wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, substitution inpara position, W is C(═O)H.

To a stirred solution of A (wherein Ar is 4-ClPhenyl, X is O, 23.4 g,182 mmol) in DMF (150 mL), 2-chloro-4-fluorobenzaldehyde (compound B;28.8 g; 182 mmol) and cesium carbonate (61 g; 187 mmol) were added. Themixture was refluxed for 4 hours and then cooled to room temperature.After dilution with brine (800 mL), the resulting precipitate wasextracted with Et₂O (4×250 mL). The organic layer was washed with brine(3×300 mL), water (2×300 mL), and then dried over MgSO₄ and concentratedin vacuo. The crude product was purified by flash chromatography(eluent:cyclohexane/ethylacetate 9/1) to afford compound 4 (20.5 g; 77mmol)

Yield=42%.

R_(f)=0.75 (9:1 cyclohexane /ethylacetate).

Compound 4a

Compound C wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H,substitution in ortho position, W is C(═O)H.

To a stirred solution of 4-chlorophenol (compound A wherein Ar is4-ClPhenyl, X is O, 20.3 g, 155 mmol) in DMF (150 mL),4-chloro-2-fluorobenzaldehyde (compound B; 25 g; 158 mmol) and potassiumcarbonate (30 g; 217 mmol) were added. The mixture was stirred for 15hours. After dilution with brine (300 mL), the resulting precipitate wasextracted with Et₂O (4×250 mL). The organic layer was washed with brine(3×300 mL), water (2×300 mL), and then dried over MgSO₄ and concentratedin vacuo to give compound 4a as an oil.

Yield=100% (41.4 g; 155 mmol)

R_(f)=0.61 (8:2 cyclohexane/ethylacetate).

B—Preparation of Compounds D

Compound 5

Compound D wherein Ar is 3,4-DiClPhenyl, X is O, substitution in orthoposition.

To a stirred solution of compound 2 (22.3 g, 83 mmol) in isopropanol(120 mL), sodium borohydride (3.16 g; 83 mmol) was added. The mixturewas stirred at room temperature for one hour, before adding water (350mL). After stirring for additional 3 hours, the aqueous layer wasextracted with Et₂O (2×300 mL). The combined organic layer was washedwith water (3×300 mL), dried over MgSO₄ and concentrated in vacuo togive compound 5 as an orange oil.

Yield=95% (21.3 g; 79 mmol).

R_(f)=0.35 (eluent:methylenechloride).

The following compound were prepared according to the proceduredescribed for compound 5:

Compound 6

Compound D wherein Ar is 3,4-DiClPhenyl, X is O, substitution in paraposition.

Reagents: compound 1 (38 g; 142 mmol) and sodium borohydride (5.37 g;142 mmol).

Yield=43% (16.6 g; 62 mmol).

R_(f)=0.56 (eluent: 95:5 methylenechloride/methanol).

Compound 7

Compound D wherein Ar is 4-ClPhenyl, X is S, substitution in paraposition;

Reagents: compound 3 (40 g; 161 mmol) and sodium borohydride (6.09 g;161 mmol). Compound 7 was generated as a yellow powder.

Yield=99% (40 g; 160 mmol).

R_(f)=0.21 (eluent: methylenechloride).

Compound 8

Compound D wherein Ar is Phenyl, X is O, substitution in ortho position.

To an ice cold solution of compound C (wherein Ar is Phenyl, X is O,substitution in ortho position, W is C(═O)OH; 25 g; 117 mmol) andN-methylmorpholine (20 ml; 180 mmol) in THF (100 mL) under N₂,isobutylchloroformate (17 ml; 131 mmol) was added. After stirring for 15minutes, sodium borohydride (12.5 g; 330 mmol) was added, followed by 50mL of water. The ice bath was removed and stirring was continuedovernight. After cooling, the mixture was made acidic with hydrochloricacid and extracted with Et₂O (2×200 mL). The combined organic layer waswashed with water (2×200 mL), dried (MgSO₄) and evaporated to dryness.The crude product was purified by flash column chromatography(eluent:ethyl acetate/cyclohexane (1/9) to produce compound 8 as ancolorless oil.

Yield=70% (16.4 g; 82 mmol).

R_(f)=0.50 (eluent: 7:3 cyclohexane/ethylacetate).

The following compound was prepared according to the procedure asdescribed for compound 8:

Compound 9

Compound D wherein Ar is Phenyl, X is O, substitution in para position.

Reagents: compound C (wherein Ar is Phenyl, X is O, substitution in paraposition, W is C(═O)OH; 38 g; 142 mmol), isobutylchloroformate (13.6 mL;105 mmol) and sodium borohydride (10 g; 264 mmol).

Yield=46% (8.6 g; 43 mmol).

R_(f)=0.58 (eluent: 1:1 ethylacetate/cyclohexane).

Compound 10

Compound D (wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, substitutionin para position)

To a stirred solution of compound 4 (20.5 g, 77 mmol) in isopropanol(100 mL), sodium borohydride (2.9 g; 77 mmol) was added. The mixture wasstirred at room temperature for one night, before adding water (350 mL).After stirring for additional 3 hours, the solvent was removed bydecantation. The resulting residue was taken into a mixture of water(400 mL) and ether (400 mL). The organic layer was washed with water(2×150 mL), dried over MgSO₄ and concentrated in vacuo to furnish an oilthat was purified by column chromatography (eluent methylenechloride) toafford compound 10 as a yellow oil after solvent evaporation.

Yield=30% (6.3 g; 23 mmol).

R_(f)=0.45 (eluent:methylenechloride).

Compound 10a

Compound D wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H,substitution in ortho position

To a stirred solution of compound 4a (41.4 g, 155 mmol) in isopropanol(250 mL), sodium borohydride (6.8 g; 180 mmol) was added. The mixturewas stirred at room temperature for one night, before adding water (1.5L). After stirring for additional 3 hours, the resulting precipitatedsolid was filtered off, washed with water and dried in vacuo to generatecompound 10a as a white powder.

Yield=63% (26.2 g; 97 mmol).

R_(f)=0.61 (eluent: 98:2 methylenechloride /methanol).

C—Preparation of Compounds E

Compound 11

Compound E wherein Ar is 4-ClPhenyl, X is O, substitution in paraposition.

To a stirred mixture of thiourea (6 g; 79 mmol), 48% HBr (34 mL) andwater (6 mL) at 60° C., compound D (Ar is 4-ClPhenyl, X is O,substitution in para position; 14.6 g; 62 mmol) prepared according toscheme A, step 1 and 2, was added portionwise. The reaction mixture wasrefluxed for one hour, cooled and filtered. The resulting residue waswashed with water (3×30 mL) and dried under vacuum to generate 21 g ofcompound 11 as the major product. It was used in the next step withoutany further purification.

D—Preparation of Compounds I—Scheme A

Example 1

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution inpara position, Y—R¹ is CH₂ COOH.

To a stirred mixture of thiourea (6 g; 79 mmol), 48% HBr (34 mL) andwater (6 mL) at 60° C., compound 6 (16.6 g; 62 mmol) was addedfractionwise. The reaction mixture was refluxed for one hour, and thencooled to room temperature and filtered. The resulting residue waswashed with water (3×30 mL) and then poured into aqueous NaOH (32%, 30mL). The resulting aqueous mixture was stirred and heated to 70° C.before adding dropwise a solution of chloracetic acid (6.8 g, 72 mmol)in aqueous sodium hydrogenocarbonate (16 mL). The mixture was thenrefluxed for one hour, cooled to room temperature, diluted with water(150 mL), acidified to pH 2 with 4N aqueous HCl and then extracted intoEt₂O (250 mL). The dried (MgSO4) organic phase was evaporated to drynessto give a residue. The crude product was purified by flashchromatography (eluent: methylenechloride/methanol (9/1) to affordExample 1 (13.2 g; 38.5 mmol) as an orange oil.

Yield=62%.

R_(f)=0.47 (eluent: 9:1 methylenechloride /methanol).

According to the process as described above, the following compoundswere prepared:

Example 2

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution inortho position; Y—R¹ is CH₂ COOH.

Reagents: compound 5 (21.3 g; 79 mmol) following the same procedure andchloracetic acid (6.8 g, 72 mmol).

Yield=49% (16.8 g; 49 mmol).

R_(f)=0.53 (eluent: 9:1 methylenechloride/methanol).

Example 3

Compound I wherein Ar is 4-ClPhenyl, X is S, q is 0, substitution inpara position, Y—R¹ is CH₂ COOH.

Reagents: compound 7 (15.6 g, 62 mmol) and chloracetic acid (4.16 g, 44mmol).

Yield=82% (16.5 g; 51 mmol of compound 12 obtained as an off-whitesolid)

R_(f)=0.44 (eluent: 90:10 methylenechloride/methanol).

Example 4

Compound I wherein Ar is Phenyl, X is O, q is 0, substitution in paraposition, Y—R¹═CH₂ COOH.

Reagents: compound 9 (8 g, 40 mmol) and chloracetic acid (4.16 g, 44mmol).

Yield=90% (9.9 g; 36 mmol).

R_(f)=0.42 (eluent: 90:10 methylenechloride/methanol).

Example 5

Compound I wherein Ar is Phenyl, X is O, q is 0, substitution in orthoposition, Y—R¹ is CH₂ COOH.

Reagents: compound 8 (8 g, 40 mmol) and chloracetic acid (4.16 g, 44mmol).

Yield=64% (8.4 g; 31 mmol).

R_(f)=0.49 (eluent: 90:10 methylenechloride/methanol).

Example 6

Compound I wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, q is 0,substitution in para position, Y—R¹═CH₂COOH.

To a stirred mixture of thiourea (2.2 g; 29 mmol), 48% HBr (12 mL) andwater (2 mL) at 60° C., compound 10 (6.3 g; 23.4 mmol) was addedfractionwise. The reaction mixture was refluxed for fifteen minutes, andthen cooled to room temperature and filtered. The resulting residue waswashed with water (3×30 mL) and then poured into aqueous NaOH (32%, 12mL). The resulting aqueous mixture was stirred and heated to 70° C.before adding dropwise a solution of sodium chloracetate (3 g, 26 mmol).The mixture was then refluxed for one hour, cooled to room temperature,diluted with water (150 mL), acidified to pH 2 with 4N aqueous HCl andthen extracted into Et₂O (250 mL). The dried (MgSO4) organic phase wasevaporated to dryness to afford Example 6 (13.2 g; 38.5 mmol) as anyellow oil after solvent evaporation.

Yield=69% (6.9 g; 20 mmol)

R_(f)=0.36 (eluent: 93:7 methylenechloride/methanol).

Example 7

Compound I wherein Ar is 4-ClPhenyl, X is O, q is 0, substitution inpara position, Y—R¹ is CH₃.

To a stirred mixture of compound 11 (7.3 g; 19.5 mmol) in 0.6N aqueoussodium hydroxyde (20 mL), dimethylsulfate (2 mL, 18 mmol) was added. Thereaction mixture was then refluxed for two hours, cooled and acidifiedwith 1N aqueous hydrochloride. The precipitate was extracted with amixture of ether (50 mL) and ethylacetate (50 mL). The organic layer waswashed with water (2×100 mL) and concentrated under vacuum. Theresulting residue was purified by column chromatography(eluent:methylene chloride) to produce 2.2 g of Example 7 as the majorproduct (oil). It was used in the next step without any furtherpurification.

Example 8 1-methanesulfinylmethyl-4-(4-chlorophenoxy)-benzene

Compound I wherein Ar is 4-ClPhenyl, X is O, q is 1, substitution inpara position, Y—R¹ is CH₃.

To a solution of Example 7 (2.2 g; 8.3 mmol) in acetic acid (30 mL), a30% by wt hydrogen peroxide solution (0.99 mL; 9.7 mmol) was added. Themixture was stirred until no more starting material was detected (HPLC),concentrated under high vacuum. The resulting residue was purified bycolumn chromatography (eluent:methylene chloride/methanol 95/5) toproduce an oil which is taken up into methylene chloride (100 mL). Theorganic phase was washed with an aqueous solutiuon of sodium hydroxide(2×50 mL), water (1×50 mL), dried (MgSO₄) and and concentrated in vacuoto produce Example 8 as a white powder.

Yield=39% (0.9 g; 3.2 mmol)

¹H-NMR (DMSO-d₆) δ: 7.45 (d, 2H), 7.3 (d, 2H), 7.0 (m, 4H), 4.2 (d, 1H),3.9 (d, 1H), 2.45 (s, 3H).

MS: 303 (M+Na).

Example 9 di[4-(4-chloro-phenoxy)-phenylmethyl]sulfoxyde

Compound I wherein Ar is 4-ClPhenyl, X is O, q is 1, substitution inpara position, Y—R¹ is CH₂[4(4-ClPhenoxy)phenyl]

0.6 g of Example 9 was obtained as a by product during the preparationprocess of example 8 as white powder.

¹H-NMR (DMSO-d₆) δ: 7.45 (d, 2H), 7.3 (d, 2H), 7.0 (m, 4H), 4.2 (d, 1H),3.8 (d, 1H).

MS 483 (M+H).

Example 10 1-methanesulfinylmethyl-4-(3,4-dichlorophenoxy)-benzene

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inpara position, Y—R¹ is CH₃ was prepared following the same multistepgeneral method as described in scheme A for Example 8 utilizing theappropriate substituted aryl alcohol.

MS: 337 (M+Na).

Example 10a

Compound I wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, q is0, substitution in ortho position, Y—R¹ is CH₂ COOH

To a stirred mixture of thiourea (6 g; 79 mmol), 48% HBr (34 mL) andwater (6 mL) at 60° C., compound 10a (17.4 g; 65 mmol) was addedportionwise. The reaction mixture was refluxed for one hour, cooled andfiltered. The resulting residue was washed with water (3×30 mL) and thenpoured into aqueous NaOH (32%, 30 mL). The resulting aqueous mixture wasstirred and heated to 70° C. before adding dropwise a solution of sodiumchloracetate (8.4 g, 72 mmol) in water (16 mL). The mixture was thenrefluxed for one hour, cooled to room temperature, diluted with water(150 mL), acidified to pH 2 with 4N aqueous HCl and then extracted intoEt₂O (250 mL). The dried (MgSO4) organic phase was evaporated to drynessto give a residue. The crude product was purified by flashchromatography (eluent: methylenechloride/methanol (9/1) to affordExample 10a as an orange powder.

Yield=57% (12.6 g; 37 mmol).

¹H-NMR (DMSO-d₆) δ: 7.0 (m, 3H), 6.75 (broad d, 1H), 6.65 (broad d, 2H),6.5 (broad s, 1H), 3.4 (s, 2H), 2.8 (s, 1H).

MS: 341 (M−1).

E—Synthesis of Compound I (q is 0)—Scheme B, Route A

Example 11

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution inpara position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a cooled solution of Example 1 (2.27 g; 6.6 mmol) in CH₂Cl₂ (50 mL),N-acetylpiperazine (0.94 g; 7.3 mmol) and EDCI (1.4 g; 7.3 mmol) wereadded. The reaction mixture was stirred until no more starting materialwas detected. The organic layer was washed with 1N HCN, water, dried(MgSO₄) and concentrated in vacuo. The crude product was purified bycolumn chromatography (eluent:methylenechloride/methanol 98.5/1.5) toproduce Example 11 as an oil.

Yield=76% (2.3 g; 5 mmol)

R_(f)=0.26 (eluent: 96:4 methylenechloride/methanol)

The following examples were prepared according to the process asdescribed for example 11:

Example 12

Compound I wherein Ar is Phenyl, X is O, q is 0, substitution in orthoposition, Y—R¹ is CH₂ CO NH(CH₂)₂OH.

Reagents: Example 5 (0.7 g, 2.6 mmol) and ethanolamine (0.18 g; 2.9mmol).

Yield=56% (0.46 g; 1.4 mmol)

R_(f)=0.5 (eluent: 90:10 methylenechloride/methanol)

Example 13

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution inpara position, Y—R¹ is CH₂ CO-1-(4-Boc)-piperazinyl.

To a cooled solution of example 1 (8.8 g; 25.6 mmol) in CH₂Cl₂ (150 mL)N-Bocpiperazine (4.8 g; 25.8 mmol), EDCI (4.9 g; 25.6 mmol) and HOBT(3.5 g; 26 mmol) were added. The reaction mixture was stirred until nomore starting material was detected. The organic layer was washed with1N HCl (2×100 mL), water (100 mL), dried (MgSO₄) and concentrated invacuo. Trituration of the resulting residue with cold Et₂O, filtrationand drying under vacuum gave Example 13 as a white solid.

Yield=70% (9 g; 18 mmol)

R_(f)=0.13 (eluent: 99:1 methylenechloride/methanol)

Example 14

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution inpara position, Y—R¹ is CH₂ CO-N-piperazinyl.

To a solution of Example 13 (2 g; 3.9 mmol) in 1,4-dioxane (20 mL),hydrogenchloride in 1,4-dioxane (4N solution; 20 mL) was added. Thereaction mixture was stirred for one hour at room temperature, thenether (200 mL) was added. Filtration and drying under vacuum gave apowder which is dissolved in water (100 mL). The aqueous layer wasbasified with NaOH (1N) and the resulting precipitate was extracted withether (150 mL). The dried (MgSO₄) organic layer was evaporated todryness to furnish Example 14 as an oil.

Yield=87% (1.4 g; 3.4 mmol)

¹H-NMR (DMSO-d₆) 6:9.5 (s, 2H), 7.7 (d, 1H), 7.4 (d, 1H), 7.3 (d, 1H),7.05 (d, 1H), 6.95 (dd, 1H), 3.75 (s, 2H), 3.7 (broad, 4H), 3.4 (s, 2H),3.15 (broad, 2H), 3.05 (broad, 2H)

Example 15

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution inortho position, Y—R¹ is CH₂ CONH₂.

To a cold solution of Example 2 (3 g, 8.7 mmol) in methanol (50 mL),thionylchloride (4.2 ml; 57 mmol) was added dropwise. After 1 hourstirring at room temperature, the solvent was removed in vacuo. The oilyresidue was taken by mixture of MeOH (50 mL) and 28% NH₄OH (50 mL) andthe reaction mixture stirred overnight. The methanol was evaporated andwater (200 mL) added. The precipitated solid was filtered, washed withwater (4×50 mL) and dried in vacuo to generate Example 15 as anoff-white solid.

Yield=77% (2.3 g; 6.7 mmol).

R_(f)=0.38 (eluent: 95:5 methylenechloride/methanol).

Example 16

Compound I wherein Ar is 4-ClPhenyl, X is S, q is 0, substitution inpara position, Y—R¹ is CH₂ CO-1-(4-acetyl)-piperazinyl.

To a cooled solution of Example 3 (2.14 g; 6.6 mmol) in CH₂Cl₂ (50 mL),N-acetylpiperazine (0.9 g; 7 mmol), EDCI (1.4 g; 7.3 mmol) and HOBT (1g; 7.4 mmol) were added. The reaction mixture was stirred until no morestarting material was detected. The organic layer was washed with 1N HCl(2×100 mL), water (100 mL), dried (MgSO₄) and concentrated in vacuo.Trituration of the resulting residue with Et₂O, filtration and dryingunder vacuum gave Example 16 as a white powder.

Yield=74% (2.15 g; 4.9 mmol)

R_(f)=0.27 (eluent: 95:5 methylenechloride/methanol).

Example 17

Compound I wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, q is 0,substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a cooled solution of Example 6 (3.18 g; 9.3 mmol) in CH₂Cl₂ (60 mL),N-acetylpiperazine (1.33 g; 10.4 mmol), EDCI (2 g; 10.4 mmol) and HOBT(1.41 g; 10.4 mmol) were added. The reaction mixture was stirred untilno more starting material was detected. The organic layer was washedwith 1N HCl, water, dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography (eluent:methylenechloride/methanol 98/2) to produce Example 17 as an oil.

Yield=75% (1.6 g; 3.5 mmol)

R_(f)=0.33 (eluent: 95:5 methylenechloride/methanol)

Example 18

Compound I wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, q is 0,substitution in para position, Y—R¹ is CH₂CONH2.

To a cooled solution of Example 6 (3.6 g; 10.5 mmol) in methanol (100mL), thionylchloride (2.2 ml; 30 mmol) was added dropwise. After 1 hourstirring at room temperature, the solvent was removed in vacuo. The oilyresidue was taken by mixture of MeOH (75 mL) and 28% NH₄OH (75 mL) andthe reaction mixture stirred overnight. The methanol was evaporated andwater (200 mL) added. The precipitated solid was filtered, washed withwater (2×50 mL) and purified by column chromatography(eluent:methylenechloride/methanol 98/2) to produce Example 18 as awhite solid.

Yield=58% (2.07 g; 6.0 mmol).

R_(f)=0.52 (eluent: 95:5 methylenechloride/methanol).

Example 18a

Compound I wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, q is0, substitution in ortho position, Y—R¹ is CH₂ CONH₂

To a cold solution of Example 10a (6.3 g, 18.3 mmol) in methanol (100mL), thionylchloride (3.8 ml; 52 mmol) was added dropwise. After 1 hourstirring at room temperature, the solvent was removed in vacuo. The oilyresidue was taken by mixture of MeOH (100 mL) and 28% NH₄OH (100 mL) andthe reaction mixture stirred overnight. The methanol was evaporated andthe residue was purified by flash chromatography(eluent:methylenechloride/methanol (95/5) to afford Example 18a as awhite powder powder.

Yield=56% (3.5 g; 10.2 mmol).

R_(f)=0.44 (eluent: 95:5 methylenechloride/methanol).

F—Preparation of Compound I (q is 1 or 2)—Scheme B, Route A

Example 192-[4-(3,4-dichloro-phenoxy)-phenylmethanesulfinyl]-1-piperazin-1-yl-ethanone

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inpara position, Y—R¹ is CH₂CO-N-piperazinyl

To a solution of Example 14 (1.4 g; 3.4 mmol) in acetic acid (10 mL), a30% by wt hydrogen peroxide solution (0.4 mL; 4 mmol) was added. Themixture was stirred until no more starting material was detected (HPLC),concentrated under high vacuum. Then water (100 mL) was added to theresidue. The aqueous solution was basified with NaOH (1N) and theprecipitate extracted with ethyl acetate (150 mL). The organic phase wasdried over MgSO4 and evaporated to dryness to give an oil. Ethanol (30mL) was added and the solution stirred before adding fumaric acid (0.11g; 0.95 mmol). The reaction mixture was stirred overnight and filtered.The resulting solid was dried under vacuum to give Example 19.

Yield=38% (0.63 g; 1.3 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (d, 1H), 7.4 (d, 2H), 7.3 (d, 1H), 7.2 (d, 2H),7.1 (dd, 1H), 6.5 (s, 1H), 4.25 (d, 1H), 4.05 (d, 1H), 3.9 (m, 2H), 3.5(broad, 4H), 2.9 (broad, 4H).

MS: 427 (M+H)

According to the oxidation procedure as described for example 19, thefollowing compounds were prepared:

Example 20 2-[4-(3,4-dichloro-phenoxy)-phenylmethanesulfinyl]-acetamide

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inortho position, Y—R¹ is CH₂CONH₂.

Reagent: Example 15 (2.3 g; 6.7 mmol) and a 30% by wt hydrogen peroxide(0.7 mL; 6.9 mmol).

Yield=79% (1.9 g; 5.3 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad s, 1H), 7.65 (d, 1H), 7.5 (broad d, 1H),7.40 (broad t, 1H), 7.35 (broad s, 1H), 7.25 (broad s, 1H), 7.20 (t,1H), 7.0 (broad, 2H), 4.30 (d, 1H), 4.05 (d, 1H), 3.75 (d, 1H), 3.55 (d,1H).

MS: 358 (M+H)

Example 20a

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, (−) enantiomer,substitution in ortho position, Y—R1 is CH₂ CONH₂

The two enantiomers of Example 20 were separated by LC-Prep.

The HPLC analysis was performed as described here:

Column Chiralpak AS (10 μm, 250×4.6 mm, D068)

Mobile phase: Methanol/ethanol 1/1

Flow rate 0.5 mL/min

UV detection 220 nm

Retention time: 8.8 min

Optical rotation [α_(D)]²⁰ =−47.

Example 20b

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, (+) enantiomer,substitution in ortho position, Y—R1 is CH₂ CONH₂

The two enantiomers of Example 20 were separated by LC-Prep.

The HPLC analysis was performed as described here:

Column Chiralpak AS (10 μm, 250×4.6 mm, D068)

Mobile phase: Methanol/ethanol 1/1

Flow rate 0.5 mL/min

UV detection 220 nm

Retention time: 10.9 min

Optical rotation [α_(D)]²⁰=+43.

Example 21N-(2-hydroxy-ethyl)-2-(2-phenoxy-phenylmethanesulfinyl)-acetamide

Compound I wherein Ar is Phenyl, X is O, q is 1, substitution in orthoposition, Y—R¹ is CH₂ CONH(CH₂)₂OH.

Reagents: Example 12 (0.46 g, 1.45 mmol) and a 30% by wt hydrogenperoxide solution (0.18 mL; 1.8 mmol).

Yield=62% (0.3 g; 0.9 mmol).

¹H-NMR (DMSO-d₆) δ: 8.25 (t, 1H), 7.45-7.25 (m, 4H), 7.2 (t, 2H), 7.0(d, 2H), 6.8 (d, 1H), 4.7 (t, 1H), 4.3 (d, 1H), 4.05 (d, 1H), 3.75 (d,1H), 3.6 (d, 1H), 3.4 (q, 2H), 3.2 (m, 2H).

MS: 356 (M+Na)

Example 221-(4-acetyl-piperazin-1-yl)-2-[4-(3,4-dichloro-phenoxy)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inpara position, Y—R¹ is CH₂ CO-1-(4-acetyl)-piperazinyl).

Reagents: Example 11 (2.3 g, 5.1 mmol) and a 30% by wt hydrogen peroxidesolution (0.6 mL; 5.9 mmol).

Yield=84% (2 g; 4.3 mmol).

¹H-NMR (DMSO-d₆) δ: 7.65 (d, 1H), 7.4 (d, 2H), 7.3 (broad s, 1H), 7.1(d, 2H), 7.0 (broad d, 1H), 4.25, (d, 1H), 4.1 (d, 1H), 4.0 (m, 2H),3.6-3.35 (broad, 8H), 2.0 (s, 3H).

MS: 469 (M+H).

Example 231-(4-acetyl-piperazin-1-yl)-2-[4-(4-chloro-phenylsulfanyl)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 4-ClPhenyl, X is S, q is 1, substitution inpara position, Y—R¹ is CH₂ CO-1-(4-acetyl)-piperazinyl).

Reagents: Example 16 (1 g; 2.3 mmol), 30% by wt hydrogen peroxidesolution (0.25 mL; 2.5 mmol).

Yield=61% (0.65 g; 1.4 mmol of Example 23 as a powder)

¹H-NMR (DMSO-d₆) δ: 7.45 (broad d, 2H), 7.3 (m, 6H), 4.25 (d, 1H), 4.05(d, 1H), 3.95 (m, 2H), 3.5 (broad, 8H), 2 (s, 3H).

MS: 473 (M+Na).

Example 241-(4-acetyl-piperazin-1-yl)-2-[4-(4-chloro-benzenesulfinyl)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 4-ClPhenyl, X is SO, q is 1, substitution inpara position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

Reagents: Example 16 (1 g, 2.3 mmol), a 30% by wt hydrogen peroxidesolution (0.25 mL; 2.5 mmol).

Yield=19% (0.2 g; 0.43 mmol of Example 24 as a powder).

¹H-NMR (DMSO-d₆) δ: 7.75 (broad d, 4H), 7.7 (d, 2H), 7.5 (d, 2H), 4.3(d, 1H), 4.1 (d, 1H),4.0 (broad s, 2H), 3.4 (broad, 8H), 2.05 (s, 3H).

MS:489 (M+Na).

Example 251-(4-acetyl-piperazin-1-yl)-2-[2-chloro-4-(4-chloro-phenoxy)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, q is 1,substitution in para position, Y—R¹ is CH₂ CO-1-(4-acetyl)-piperazinyl;

To a solution of Example 17 (3.15 g; 6.9 mmol) in acetic acid (20 mL), a30% by wt hydrogen peroxide solution (0.82 mL; 8.1 mmol) was added. Themixture was stirred until no more starting material was detected (HPLC),and then concentrated under high vacuum. The resulting residue was takeninto a mixture of water solution of sodium bicarbonate (200 mL) andethyl acetate (200 mL). The organic layer was washed with water (1×100mL), dried over MgSO₄ and concentrated in vacuo to afford compound 25 asa white powder.

Yield=83% (2.7 g; 5.8 mmol).

¹H-NMR (DMSO-d₆) δ: 7.5 (dd, 2H), 7.3 (m, 2H), 7.1 (dd, 2H), 6.8 (broad,1H), 4.5 (d, 1H), 4.3 (d, 1H), 4.2 (m, 2H), 3.5 (broad, 8H), 2 (s, 3H).

MS 469 (M+H).

Example 262-[2-chloro-4-(4-chloro-phenoxy)-phenylmethanesulfinyl]-acetamide

Compound I wherein Ar is 4-ClPhenyl; R² is 3-Cl, X is O, q is 1,substitution in para position, Y—R¹ is CH₂CONH2.

Reagents: Example 18 (2.07 g; 6.0 mmol) and a 30% by wt hydrogenperoxide (0.7 mL; 6.9 mmol).

Yield=91% (1.95 g; 5.4 mmol).

¹H-NMR (DMSO-d₆) δ: 7.75 (broad s, 1H), 7.5 (broad d, 2H), 7.3 (m, 3H),7.15 (broad d, 2H), 6.8 (broad m, 1H), 4.35 (d, 1H), 4.30 (d, 1H), 3.8(d, 1H), 3.6 (d, 1H).

MS: 380 (M+Na).

Example 271-(4-acetyl-piperazin-1-yl)-2-[4-(3,4-dichloro-phenoxy)-phenylmethanesulfonyl]-ethanone

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 2, substitution inpara position, Y—R¹ is CH₂ CO-1-(4-acetyl)-piperazinyl;

To a solution of Example 22 (0.85 g; 1.8 mmol) in acetic acid (20 mL), a30% by wt hydrogen peroxide solution (0.56 mL; 5.5 mmol) was added. Themixture was stirred at 55° C. until no more starting material wasdetected (HPLC), and then concentrated under high vacuum. The resultingresidue was taken into a mixture of water solution of sodium bicarbonate(200 mL) and ethyl acetate (200 mL). The organic layer was washed withwater (1×100 mL), dried over MgSO₄ and concentrated in vacuo. Theresulting residue was purified by column chromatography(eluent:methylenechloride/methanol 95/5) to generate Example 27 as awhite powder.

Yield=71% (0.62 g; 1.3 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (d, 1H), 7.45 (d, 2H), 7.30 (broad s, 1H), 7.1(d, 2H), 7.0 (broad d, 1H), 4.7 (s, 2H), 4.35 (broad d, 2H), 3.6-3.4(broad m, 8H), 2 (s, 3H).

MS: 507 (M+Na).

Example 27a

Compound I wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, q is1, substitution in ortho position, Y—R¹ is CH₂ CONH₂

To a solution of Example 10a (3.5 g; 10.2 mmol) in acetic acid (30 mL),a 30% by wt hydrogen peroxide solution (1.36 mL; 13.3 mmol) was added.The mixture was stirred until no more starting material was detected(HPLC), and then concentrated under high vacuum. The residue wastriturated in diethyloxide the resulting precipitated solid was filteredoff, washed with diethyloxide and dried in vacuo to generate Example 27aas a white powder.

Yield=93% (3.4 g; 9.5 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad s, 1H), 7.45 (broad m, 3H), 7.3 (broad s,1H), 7.25 (broad d, 1H), 7.1 (broad d, 2H), 6.9 (broad s, 1H), 4.30 (d,1H), 4.05 (d, 1H), 3.75 (d, 1H), 3.5 (d, 1H).

MS: 379.8 (M+Na).

Example 27b

Compound I wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, q is2, substitution in ortho position, Y—R¹ is CH₂ CONH₂

To a solution of Example 27a (0.07 g; 0.2 mmol) in acetic acid (5 mL), a30% by wt hydrogen peroxide solution (0.085 mL; 0.8 mmol) was added. Themixture was stirred at 55° C. until no more starting material wasdetected (HPLC), and then cooled to room temperature. The resultingprecipitated solid was filtered off, washed with diethyl oxide and driedin vacuo to generate Example 27b as a white powder.

Yield=65% (0.48 g; 0.13 mmol).

¹H-NMR (DMSO-d₆) δ: 7.8 (broad s, 1H), 7.5 (broad m, 4H), 7.25 (broad d,1H), 7.1 (broad d, 2H), 6.8 (broad s, 1H), 4.75 (s, 2H), 4.1 (s, 2H).

MS: 396 (M+Na).

G—Synthesis of Compounds I (q is 0, 1, 2)—Scheme B—Route B

Example 28

Compound I wherein Ar is Phenyl, X is O, q is 1, substitution in paraposition, Y—R¹ is CH₂ COOH.

To a solution of Example 4 (4 g; 14.6 mmol) in acetic acid (30 mL) a 30%by wt hydrogen peroxide solution (1.9 mL; 18 mmol) was added. Themixture was stirred until no more starting material was detected (HPLC),concentrated at high vacuum and triturated with ether to give Example 28as an off-white solid.

Yield=82% (3.5 g; 12 mmol)

R_(f)=0.15 (eluent: 90:10 methylenechloride/methanol)

Example 29 N-isopropropyl-2-(4-phenoxy-phenylmethanesulfinyl)-acetamide

Compound I wherein Ar is Phenyl, X is O, q is 1, substitution in paraposition, Y—R¹ is CH₂CO NHCH(CH₃)₂.

To a cooled solution of Example 28 (0.4 g; 1.4 mmol) in CH₂Cl₂ (25 mL),isopropylamine (0.095 g; 1.6 mmol), EDCI (0.31 g; 1.6 mmol) and HOBT(0.22 g; 1.6 mmol) were added. The reaction mixture was stirred until nomore starting material was detected. Methylene chloride (100 mL) wasadded to the reaction mixture and the organic layer washed with 1N HCl(2×100 mL), water (100 mL), dried (MgSO₄) and concentrated in vacuo. Theresulting residue was purified by column chromatography (eluent:methylenechloride/methanol (93/7) to generate Example 29 as a powder.

Yield=63% (0.35 g; 1 mmol).

¹H-NMR (DMSO-d₆) δ: 8.15 (d, 1H), 7.45 (broad t, 2H), 7.35 (broad d,2H), 7.15 (broad t, 1H),7.0 (broad t, 4H), 4.2 (d, 1H), 3.95 (d, 1H),3.85 (m, 1H), 3.55 (d, 1H), 3.45 (d, 1H), 1.0 (d, 6H).

MS: 354 (M+Na).

Example 30 [4-(3,4-dichloro-phenoxy)-phenylmethanesulfinyl]-acetic acid

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inpara position, Y—R¹ is CH₂ COOH.

To a solution of Example 1 (0.94 g; 2.7 mmol) in acetic acid (20 mL) a30% by wt hydrogen peroxide solution (0.32 mL; 3.2 mmol) was added. Themixture was stirred until no more starting material was detected (HPLC),concentrated at high vacuum and triturated with ether to give Example 30as an off-white solid.

Yield=57% (0.55 g; 1.53 mmol)

¹H-NMR (DMSO-d₆) δ: 7.7 (d, 1H), 7.4-7.3 (m, 3H), 7.35 (broad d, 2H),7.1 (d, 2H), 7.0 (broad d, 1H), 4.2 (d, 1H), 4.1 (d, 1H), 3.8 (d, 1H),3.6 (d, 1H).

MS: 381 (M+Na).

Example 30a [2-(3,4-dichloro-phenoxy)-phenylmethanesulfinyl]-acetic acid

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inortho position, Y—R1 is CH₂ COOH

To a solution of Example 2 (20.58 g, 60 mmol) in glacial acetic acid (60mL) was added 35% aqueous hydrogen peroxide (6.6 mL) at roomtemperature.The mixture was stirred until no more starting material wasdetected (TLC). After 2 h of stirring, the sulfoxyde precipitated; theprecipitate was filtered, washed with water and diisopropyl oxidesuccessively, dried under vacuum to yield Example 30a (white powder;18.36 g)

Yield=85%.

R_(t): 12.25 min.

¹H-NMR (DMSO) δ (ppm): 7.65 (d, 1H) 7.45 (d, 1H), 7.4 (t, 1H), 7.3-7.15(m, 2H), 7.05-6.9 (m, 2H), 4.25 (d, 1H), 4.1 (d, 1H), 3.9 (d, 1H), 3.65(d, 1H).

Example 30b [2-(3,4-dichloro-phenoxy)-phenylmethanesulfonyl]-acetic acid

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 2, substitution inortho position, Y—R1 is CH₂ COOH

To a suspension of Example 30a (1.79 g, 5 mmol) in glacial acetic acid(5 mL) at room temperature was added 35% aqueous hydrogen peroxide (1.5mL). The mixture was heated to 50° C. for 4 h until no more startingmaterial was detected (HPLC). After concentration, the residue wastriturated in water to give a precipitate that was filtered, washed withwater and diisopropyl ether successively, dried under vacuum to yieldExample 30b (white powder; 0.78 g)

Yield=42%.

R_(t): 13.5 min.

¹H-NMR (DMSO) δ (ppm): 7.6 (d, 1H) 7.5 (d, 1H), 7.4 (t, 1H), 7.3-7.2 (m,2H), 7.05-6.9 (m, 2H), 4.7 (s, 2H), 4.25 (s, 2H).

MS: 373 (M−H); 749 (2M+H)

Example 30c

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution inortho position, Y—R1 is CH₂ COO (1R,2S,5R) Menthyl

To a stirred solution of Example 2 (5 g; 14.6 mmol) in DMF (30 mL), TBTU(o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate) (7g; 21.8 mmol), N-methyl morpholine (2.45 mL; 22.2 mmol) and (1R, 2S, 5R)(−) menthol were added. The reaction mixture was stirred for fifteenhours, and then ethyl acetate (200 mL) and brine (200 mL) were addedinto it. The resulting organic layer was evaporated and the residue waspurified by flash chromatography (eluent:cyclohexane/ethyl acetate(95/5) to afford Example 30c as a yellow oil.

Yield=60% (4.2 g; 8.7 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad d, 1H), 7.45 (broad d, 1H), 7.30 (broadt, 1H), 7.2 (broad, 2H), 6.95 (broad m, 2H), 4.55 (m, 1H), 3.8 (s, 2H),3.25 (s, 2H), 1.8 (broad m, 2H), 1.7 (broad m, 2H), 1.45 (broad, 1H),1.30 (broad t, 1H), 1.0 (broad, 1H), 0.85 (broad t, 8H), 0.70 (d, 3H).

Example 30d

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inortho position, Y—R1is CH₂ COOH, enantiomer (−).

To a solution of Example 30c (2.09 g; 4.35 mmol) in acetic acid (25 mL),a 30% by wt hydrogen peroxide solution (0.39 mL; 4.4 mmol) was added.The mixture was stirred at room temperature until no more startingmaterial was detected (HPLC), and then the solvent was evaporated. Theresidue was purified by flash chromatography (eluent: cyclohexane/ethylacetate (8/2) to afford a mixture of two diastereoisomers which wereseparated by LC Preparative. The HPLC analysis was performed asdescribed here:

Column AGP-Chiral (5 μm, 150×4. mm)

Mobile phase: (aqueous ammonium acetate 0.1M)/n-Butanol: 98.5/1.5

Flow rate 0.8 mL/min

UV detection 230 nm

Results: Diastereoisomer 1: retention time 8.1 min,

-   -   Diastereosomer 2: retention time 9.7 min.

To a solution of diastereoisomer 2 in methanol (28 mL) andtetrahydrofuran (75 mL), barium hydroxide octahydrate (0.25 g; 0.8 mmol)was added. The mixture was stirred at room temperature until no morestarting material was detected (HPLC), and then the solvent wasevaporated. Methylene chloride (50 mL) was added into it. The organiclayer was washed with water (1×50 mL), dried over MgSO₄ and concentratedin vacuo. The resulting residue was washed with ether to afford a whitepowder. To a mixture of this powder in water (17 mL) and ethanol (5 mL),an aqueous hydrochloric acid solution (3 mL, 0.5N) was added. Themixture was stirred at room temperature for 6 hours. The resultingprecipitated solid was filtered off, washed with water and dried invacuo to generate Example 30d as a white powder.

Yield=20% (0.317 g; 0.89 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad d, 1H), 7.45 (broad d, 1H), 7.30 (broadt, 1H), 7.25 (broad m, 2H), 7.0 (broad t, 2H), 4.25 (d, 1H), 4.1 (d,1H), 3.95 (s, 1H), 3.7 (s, 1H).

Optical rotation [α_(D)]²⁰=−49.

Enantiomeric excess >98%.

Example 30e

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inortho position, Y—R1 is CH₂ COOH, enantiomer (+).

To a solution of diastereoisomer 1 (isolated during the synthesis ofExample 30d) in ethanol (5 mL) and water (7.5 mL), sodium hydroxide wasadded. The mixture was stirred at room temperature until no morestarting material was detected (HPLC). Aqueous hydrochloric acidsolution (10 mL, 0.5N) and methylene chloride (50 mL) were added intoit. The organic layer was washed with water (1×50 mL), dried over MgSO₄and concentrated in vacuo. The resulting residue was triturated indiethyl oxide and the precipitated solid was filtered off, washed withdiethyl oxide and dried in vacuo to generate Example 30e as a whitepowder.

Yield=16% (0.255 g; 0.71 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad d, 1H), 7.45 (broad d, 1H), 7.30 (broadt, 1H), 7.25 (broad m, 2H), 7.0 (broad t, 2H), 4.25 (d, 1H), 4.1 (d,1H), 3.95 (s, 1H), 3.7 (s, 1H).

Optical rotation [α_(D)]²⁰=+46.

Enantiomeric excess >98%.

Example 30f[2-(3,4-dichloro-phenoxy)-phenylmethanesulfanyl]-N,N-dimethyl-acetamide

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution inortho position, Y—R1is CH₂ CON(CH₃)₂

To a cooled (ice-bath) solution of Example 2 (3.43 g, 10 mmol) in CH₂Cl₂(60 mL), was added successively dimethylamine (0.495 g, 1.25 mL, 11mmol), EDCI (2.1 g, 11 mmol) and HOBT (1.48 g, 11 mmol). The coolingbath was removed and the reaction mixture was stirred at roomtemperature for one night. It was then diluted with CH₂Cl₂ (40ml),washed successively with water (60 ml), aqueous NaHCO₃, water (60ml) anddried over Na₂SO₄. On concentration, the solution generated an orangeoil that was triturated in diisopropyl ether to yield the title compoundExample 30f (2.9 g; beige powder).

Yield=78%.

R_(f) (CH₂Cl₂/CH₃OH 9/1)=0.65.

R_(t): 15.86 min.

Example 30g[2-(3,4-dichloro-phenoxy)-phenylmethanesulfinyl]-N,N-dimethyl-acetamide

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution inortho position, Y—R1 is CH₂ CON(CH₃)₂

To a suspension of Example 30f (2.91 g, 7.9 mmol) in glacial acetic acid(10 mL) at room temperature was added 35% aqueous hydrogen peroxide(0.87 mL). The mixture was stirred for 3 h until no more startingmaterial was detected (HPLC). After concentration, the residue wastriturated in diisopropyl ether to give a solid that was filtered,washed with diisopropyl ether and dried under vacuum to yield Example30g (slightly beige powder; 0.78 g).

Yield=86%.

R_(t): 12.32 min.

¹H-NMR (DMSO) δ (ppm): 7.65 (d, 1H) 7.45 (d, 1H), 7.4 (t, 1H), 7.25-7.2(m, 2H), 7 (dd, 2H), 4.25 (d, 1H), 4.15 (d, 1H), 3.95 (s, 2H), 2.95 (s,3H), 2.75 (s, 3H).

MS:408 (M+Na).

Compounds 31 through 112 were prepared following the same multistepgeneral method as described in scheme B utilizing the appropriatesubstituted amine —NR¹²R¹³ in steps 5 or 6. The analytical data ispresented by each compounds molecular formula and masse spectrum (M+H)or (M+Na) as shown in the following Table 2. TABLE 2 Example N^(o)Molecular Formula Peak Mass Scheme B, route A 31 C₁₉H₂₁NO₃S M + H 344 32C₁₅H₁₅NO₃S M + H 290 33 C₁₇H₁₉NO₃S M + H 318 34 C₁₈H₂₁NO₃S M + H 332 35C₂ ₁H₂₄N₂O₄S M + H 401 36 C₁₆H₁₇NO₄S M + Na 342 37 C₂₂H₂₆N₂O₅S M + Na453 38 C₂₀H₂₄N₂O₄S.C₄H₄O₄ M + H 389 39 C₁₅H₁₃Cl₂NO₃S M + Na 380 40C₂₁H₂₂Cl₂N₂O₄S M + H 469 41 C₂₀H₂₁Cl₂N₃O₄S M + H 470 42 C₁₆H₁₇NO₄S M +Na 342 43 C₁₅H₁₄ClNO₃S M + Na 346 44 C₁₅H₁₅NO₄S M + Na 328 45C₁₅H₁₄ClNO₃S M + H 324 46 C₂₁H₂₃ClN₂O₄S M + Na 457 47C₁₉H₂₁ClN₂O₃S.C₄H₄O₄ M + H 393 48 C₂₁H₂₃FN₂O₄S M + H 419 49 C₂₁H₂₃FN₂O₄SM + H 419 50 C₁₅H₁₄FNO₃S M + Na 330 51 C₁₅H₁₄FNO₃S M + Na 330 52C₁₉H₁₇NO₃S M + Na 362 53 C₂₆H₂₇NO₄S M + Na 473 54 C₁₉H₁₇NO₃S M + Na 36255 C₂₁H₁₉NO₃S M + Na 388 56 C₂₁H₁₉NO₃S M + H 366 57 C₂₁H₂₃ClN₂O₄S M + H435 58 C₂₅H₂₆N₂O₄S M + Na 473 59 C₂₇H₂₈N₂O₄S M + H 477 60 C₂₇H₂₈N₂O₄SM + Na 499 61 C₂₁H₂₃ClN₂O₄S M + Na 457 62 C₂₁H₂₆N₂O₄S.HCl M + H 403 63C₂₂H₂₄Cl₂N₂O₅S M + H 499 64 C₂₁H₂₅FN₂O₄S.HCl M + H 421 65C₂₁H₂₄Cl₂N₂O₄S.HCl M + H 471 66 C_(2O)H₂₃FN₂O₃S.HCl M + H 391 67C₁₅H₁₄ClNO₃S M + Na 346 68 C₂₂H₂₅FN₂O₅S M + H 449 69 C₂₃H₂₈N₂O₆S M + Na483 70 C₂₂H₂₅ClN₂O₄S₂ M + Na 503 71 C₂₂H₂₅ClN₂O₅S₂ M + Na 519 72C₂₂H₂₄Cl₂N₂O₅S M + Na 521 73 C₁₉H₂₁ClN₂O₂S₂ M + H 409 74 C₂₁H₂₂Cl₂N₂O₄SM + Na 491 75 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 76 C₁₅H₁₃Cl₂NO₃S M + Na 380 77C₁₅H₁₃Cl₂NO₃S M + Na 380 78 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 79 C₂₁H₂₂Cl₂N₂O₄SM + H 469 80 C₁₅H₁₃Cl₂NO₃S M + Na 380 81 C₁₅H₁₃Cl₂NO₃S M + H 358 82C₂₁H₂₂Cl₂N₂O₄S M + H 469 83 C₂₁H₂₂Cl₂N₂O₄S M + H 469 84 C₁₅H₁₃Cl₂NO₃SM + Na 380 85 C₁₅H₁₃Cl₂NO₃S M + H 358 86 C₂₁H₂₂Cl₂N₂O₄S M + H 469 87C₂₁H₂₂Cl₂N₂O₃S₂ M + H 485 88 C₁₅H₁₃Cl₂NO₃S M + Na 380 89 C₁₅H₁₃Cl₂NO₂S₂M + Na 396 90 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 91 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 92C₁₅H₁₃Cl₂NO₃S M + Na 380 93 C₁₅H₁₃Cl₂NO₄S M + Na 396 94 C₁₅H₁₃Cl₂NO₃SM + Na 380 95 C₂₁H₂₃FN₂O₅S M + Na 457 96 C₂₁H₂₂Cl₂N₂O₅S M + Na 507 97C₁₅H₁₅NO₃S M + H 290 98 C₁₉H₂₁NO₃S M + H 344 99 C₁₇H₁₉NO₃S M + H 318100  C₁₇H₁₉NO₃S M + H 318 101  C₁₉H₂₁NO₃S M + H 344 102  C₁₅H₁₅NO₃S M +Na 312 103  C₁₇H₁₆N₂O₃S M + Na 351 104  C₁₈H₂₁NO₃S M + H 332 105 C₁₉H₂₃NO₃S M + H 346 106  C_(2O)H₂₃NO₄S M + H 374 107  C₂₁H₂₄N₂O₄S M +Na 423 108  C₁₇H₁₉NO₄S M + H 334 109  C_(2O)H₂₃NO₄S M + H 374 109aC₁₅H₁₄ClNO₃S M + Na 346 109b C₁₅H₁₃ClFNO₃S M + Na 364 109c C₁₅H₁₃ClFNO₃SM + Na 364 109d C₁₅H₁₃ClFNO₄S M + Na 380 109e C₁₅H₁₂ClF2NO₃S M + Na381.8 109f C₁₅H₁₃Cl₂NO₄S M + Na 395.7 Scheme B, route B 110  C₂₁H₂₄N₂O₄SM + Na 423 111  C₁₇H₁₉NO₄S M + Na 356 112  C₂₀H₂₃NO₄S M + Na 396 112aC₁₆H₁₅Cl₂NO₃S M + Na 394 2M + Na 766 112b C₁₉H₂₁Cl₂NO₃S M + Na 436 2M +Na 851II—Compounds Prepared According to Scheme C.

Examples 113 to 149 were synthesized according to Scheme C.

A—Preparation of Compound J

Compound 12

Compound J wherein Y—R¹ is CH₂ COOCH₃, NO₂ is in ortho position, R² andR³ are H.

To a stirred solution of 2-nitrobenzyl bromide (43.2 g; 200 mmol) in dryacetone (200 mL), methylthioglycolate (19 ml; 212 mmol), potassiumiodide (0.2 g; 1.2 mmol) and potassium carbonate (27.6 g; 200 nmmol)were added. The reaction mixture was refluxed for 4 hours and then thesolvent removed. The resulting residue was taken into a mixture of water(500 mL) and ether (500 mL). The organic layer was washed with water,dried over MgSO₄ and concentrated in vacuo to give compound 12 as anorange oil.

Yield: 100% (48.2 g; 199.9 mmol)

R_(f)=0.55 (eluent: methylenechloride)

Compound 13

Compound J wherein Y—R¹ is CH₂ COOH, NO₂ is in ortho position, R² and R³are H.

To a stirred solution of 2-nitrobenzyl bromide (25 g; 116 mmol) in dryacetone (100 mL), thioglycolic acid (8.5 mL; 122 mmol), potassium iodide(0.09 g; 0.5 mmol) and potassium carbonate (17.5 g; 127 mmol) wereadded. The reaction mixture. was refluxed overnight and the solvent wasremoved. The resulting residue was taken into water (500 mL) and thecooled aqueous mixture acidified with hydrochloric acid 4N to pH 2. Theprecipitate was extracted with ethylacetate (500 mL) and the organiclayer washed with water (2×200 mL), dried over MgSO4 and concentrated invacuo to furnish an oil that was purified by column chromatography(eluent: methylenechloride/methanol (9/1) to afford compound 13 as ayellow powder after solvent evaporation.

Yield: 76% (19.9 g; 88 mmol).

R_(f)=0.35 (eluent: 9:1 methylenechloride:methanol).

Compound 13a

Compound J wherein Y—R¹ is CH₂ COOCH₃, NO₂ is in para position, R² andR³ are H.

To a stirred solution of 4-nitrobenzyl bromide (43.2 g; 200 mmol) in dryacetone (200 mL), methylthioglycolate (19 mL; 212 mmol), potassiumiodide (0.2 g; 1.2 mmol) and potassium carbonate (27.6 g; 200 mmol) wereadded. The reaction mixture was refluxed for 4 hours and then thesolvent removed. The resulting residue was taken into a mixture of water(500 mL) and ether (500 mL). The organic layer was washed with water,dried over MgSO₄ and concentrated in vacuo to give compound 13a as anorange oil.

Yield: 100% (48.2 g; 199.9 mmol)

R_(f)=0.95 (eluent: 9:1 methylenechloride/methanol)

B—Preparation of Compound K

Compound 14

Compound K wherein Y—R¹ is CH₂CONH₂, NO₂ is in ortho position, R² and R³are H.

To a stirred solution of compound 12 (20 g, 82.9 mmol) in methanol (50mL), 28% NH₄OH (50 mL) was added. The reaction mixture was stirredovernight, the methanol evaporated and water (250 mL) added into themixture. The precipitated solid was filtered off, washed with water anddried in vacuo to generate compound 14 as a yellow powder.

Yield: 81% (15.1 g; 67 mmol)

R_(f)=0.28 (eluent: 95:5 methylenechloride/methanol)

Compound 15

Compound K wherein Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl, NO₂ is inortho position, R² and R³ are H.

To a cooled solution of compound 13 (12 g, 53 mmol) in CH₂Cl₂ (200 mL),N-acetylpiperazine (7.3 g; 57 mmol), EDCI (10.9 g; 57 mmol) and HOBT(7.8 g; 58 mmol) were added. The reaction mixture was stirred until nomore starting material was detected. The organic layer was washed with1N HCl (2×100 mL), water (100 mL), dried (MgSO₄) and concentrated invacuo. Trituration of the resulting residue with Et₂O, filtration anddrying under vacuum gave compound 15 as an off-white solid.

Yield: 92% (16.4 g; 49 mmol).

R_(f)=0.23 (eluent: 97:3 methylenechloride/methanol).

Compound 15a

Compound K wherein Y—R¹ is CH₂CONH₂, NO₂ is in para position, R² and R³are H.

To a stirred solution of compound 13a (48.2 g, 200 mmol) in methanol(250 mL), 28% NH₄OH (250 mL) was added. The reaction mixture was stirredovernight, the methanol evaporated and water (700 mL) added into themixture. The precipitated solid was filtered off, washed with water anddried in vacuo to generate compound 15a as an orange powder.

Yield: 78% (35.5 g; 157 mmol)

R_(f)=0.55 (eluent: 9:1 methylenechloride/methanol).

C—Preparation of Compound L

Compound 16

Compound L wherein Y—R¹ is CH₂CONH₂, q is 1, NO₂ is in ortho position,R² and R³ are H.

To a solution of compound 14 (8 g; 35.4 mmol) in acetic acid (120 mL), a30% by wt hydrogen peroxide solution (4.5 mL; 40 mmol) was added. Thereaction mixture was stirred overnight and concentrated under highvacuum. Trituration of the resulting residue with ethylacetate,filtration and drying under vacuum gave compound 16 as a yellow powder.

Yield: 90% (7.86 g; 32 mmol).

R_(f)=0.34 (eluent: 9:1 methylenechloride/methanol).

Compound 17

Compound L wherein Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl, q is 1, NO₂is in ortho position, R² and R³ are H.

To a solution of compound 15 (8.2 g; 24.3 mmol) in acetic acid (60 mL),a 30% by wt hydrogen peroxide solution (2.8 mL; 28 mmol) was added. Thereaction mixture was stirred for two hours and concentrated at highvacuum. The resulting residue was purified by column chromatography(eluent: with methylenechloride/methanol (9/1) to afford compound 17 asa yellow powder.

Yield: 74% (6.4 g; 18 mmol).

R_(f)=0.40 (eluent: 9:1 methylenechloride/methanol).

D—Preparation of Compound M′

Compound 17a

Compound M wherein Y—R¹ is CH₂CONH₂, q is 0, NH₂ is in para position, R²and R³ are H.

To a stirred solution of compound 15a (5.5 g, 24 mmol) in acetic acid(60 mL) and water (120 mL), iron (6.7 g, 120 mmol) was added. Thereaction mixture was refluxed for 15 minutes. The iron was removed byfiltration on a pad of Celite, and the filtrate was evaporated. Theresulting residue was purified by column chromatography (eluent:methylenechloride/methanol (9/1) to generate compound 17a as a greypowder.

Yield: 71% (3.36 g; 17 mmol mmol).

R_(f)=0.46 (eluent: 9:1 methylenechloride/methanol).

E—Preparation of Compound M

Compound 18

Compound M wherein Y—R¹ is CH₂CONH₂, q is 1, NH₂ is in ortho position,R² and R³ are H.

Compound 16 wherein (7.86 g, 32.5 mmol) in a mixture of DMF (50 mL) andMeOH (50 mL) was reduced in the presence of 10% Pd/C (1.6 g) in anautoclave under hydrogen pressure (50 PSI) for 12 hours. The catalystwas removed by filtration on a pad of Celite, and the filtrate wasevaporated. Trituration of the resulting residue with ethylacetate,filtration and drying under vacuum gave compound 18 as an off-whitesolid.

Yield: 80% (5.6 g; 26 mmol).

R_(f)=0.25 (eluent: 5.6 g; 26 mmol).

Compound 19

Compound M wherein Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl, q is 1, NH₂is in ortho position, R² and R³ are H.

Compound 17 (2.1 g, 5.9 mmol) in MeOH (50 mL) was reduced in thepresence of 10% Pd/C (0.2 g) in an autoclave under an hydrogen pressure(50 PSI) for 18 hours. The catalyst was removed by filtration on a padof Celite, and the filtrate was evaporated. The resulting residue waspurified by column chromatography (eluent: methylenechloride/methanol(96/4) to generate compound 19 as a white powder.

Yield: 68% (1.3 g; 4 mmol).

R_(f)=0.29 (eluent: 9:1 methylenechloride/methanol).

Compound 19a

Compound M wherein Y—R¹ is CH₂CONH₂, q is 1, NH₂ is in para position, R²and R³ are H.

To a solution of compound 17a (1 g; 5.09 mmol) in acetic acid (15 mL), a30% by wt hydrogen peroxide solution (0.6 mL; 5.9 mmol) was added. Thereaction mixture was stirred for three hours and then diethyloxide wasadded into the mixture. The precipitated solid was filtered off, washedwith diethyloxide and dried in vacuo to generate compound 19a as anyellow powder.

Yield: 65% (0.7 g; 3.3 mmol).

R_(f)=0.20 (eluent: 9:1 methylenechloride/methanol).

F—Preparation of Compound I

Example 113N-(2-carbamoylmethanesulfinylmethyl-phenyl)-4-chloro-benzamide

Compound I wherein Ar is 4-ClPhenyl, X is CONH, q is 1, substitution inortho position, R² and R³ are H, Y—R¹ is CH₂ CO NH₂.

To a stirred solution of compound 18 (1 g; 4.7 mmol) in CH₂Cl₂ (50 mL)were added pyridine (0.76 mL; 9.4 mmol) and 4-chlorobenzoylchloride (0.6mL; 4.7 mmol). The reaction mixture was stirred for one hour andfiltered. The resulting solid was washed with water andmethylenechloride and dried under vacuum to give Example 113 as a solid.

Yield: 81% (1.32 g; 3.8 mmol).

¹H-NMR (DMSO-d₆) δ: 10.6 (s, 1H), 8.0 (broad d, 2H), 7.75 (broad, 2H),7.6 (broad d, 2H), 7.4 (broad, 3H), 7.25 (broad, 1H), 4.55 (d, 1H), 4.3(d, 1H), 3.8 (d, 1H), 3.5 (d, 1H).

MS: 373 (M+Na).

The following examples were prepared according to the procedure asdescribed for Example 113.

Example 114N-(2-carbamoylmethanesulfinylmethyl-phenyl)-3,4-dimethoxy-benzamide

Compound I wherein Ar is 3,4-DiOCH₃Phenyl, X is CONH, q is 1,substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CONH₂.

Reagents: compound 18 (1 g; 4.7 mmol) and 3,4-dimethoxybenzoyl chloride(0.94 g; 4.7 mmol). Example 114 is a solid.

Yield: 49% (0.87 g; 2.3 mmol).

¹H-NMR (DMSO-d₆) δ: 10.5 (s, 1H), 7.8 (d, 1H), 7.75 (broad, 1H), 7.6 (d,1H), 7.55 (broad, 1H), 7.35 (broad, 3H), 7.2 (t, 1H), 7.1 (d, 1H), 4.5(d, 1H), 4.3 (d, 1H), 3.85 (s, 6H), 3.75 (d, 1H).

MS: 399 (M+Na)

Example 115 Naphtalene-2-carboxylic acid(2-carbamoylmethanesulfinylmethyl-phenyl)-amide

Compound I wherein Ar is 2-Naphthyl, X is CONH, q is 1, substitution inortho position, R² and R³ are H, Y—R¹ is CH₂CONH₂.

Reagents: compound 18 (1 g; 4.7 mmol) and 2-naphthoylchloride (0.92 g;4.7 mmol). Example 115 is a solid.

Yield: 58% (1 g; 2.7 mmol)

¹H-NMR (DMSO-d₆) δ: 10.75 (s, 1H), 8.7 (s, 1H), 8.1 (m, 3H), 8.05 (d,1H), 7.8 (d, 1H), 7.75 (s, 1H), 7.60 (m, 2H), 7.45 (m, 3H), 7.30 (t,1H), 4.55 (d, 1H), 4.30 (d, 1H), 3.8 (d, 1H), 3.55 (d, 1H).

MS: 367 (M+H).

Example 116N-{2-[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethanesulfinylmethyl]-phenyl}-4-chloro-benzamide

Compound I wherein Ar is 4-ClPh, X is CONH, q is 1, substitution inortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred solution of compound 19 (1 g; 3.7 mmol) in CH₂Cl₂ (40 mL),pyridine (0.76 mL; 9.4 mmol) and 4-chlorobenzoylchloride (0.6 mL; 4.7mmol) were added. The reaction mixture was stirred for one hour and thenthe solvent was removed. Trituration of the resulting residue withethylacetate, filtration and drying under vacuum gave Example 116 as apowder.

Yield: 65% (0.92 g; 2 mmol).

¹H-NMR (DMSO-d₆) δ: 10.55 (s, 1H), 8.0 (d, 2H), 7.75 (d, 1H), 7.65 (dd,2H), 7.45 (m, 2H), 7.25 (t, 1H), 4.45 (m, 1H), 4.35 (m, 1H), 4.2 (d,1H), 4.1 (d, 1H), 3.45 (broad, 8H), 2.0 (s, 3H).

MS: 484 (M+Na).

Examples 117 through 129 were prepared following the same multistepgeneral method as described for Example 116 utilizing the appropriatesubstituted amine —NR¹²R¹³ and the appropriate benzoyl chloride in step4. The analytical data is presented by each compounds molecular formulaand masse spectrum (M+H) or (M+Na) as shown in the following Table 3.TABLE 3 Example N^(o) Molecular Formula Peak Mass 117 C₁₆H₁₄F₂N₂O₃S M +H 353 118 C₁₈H₂₀N₂O₅S M + H 377 119 C₁₉H₂₂N₂O₆S M + H 407 120C₁₈H₂₀N₂O₅S M + H 377 121 C₂₄H₂₉N₃O₆S M + H 488 122 C₂₄H₂₉N₃O₆S M + H488 123 C₂₂H₂₄FN₃O₄S M + H 446 124 C₂₂H₂₃Cl₂N₃O₄S M + H 496 125C₁₈H₂₀N₂O₅S M + H 377 126 C₁₆H₁₅FN₂O₃S M + H 335 127 C₁₆H₁₄Cl₂N₂O₃S M +Na 407 128 C22H23Cl2N3O4S M + Na 518 129 C22H24FN3O4S M + Na 468

Example 130N-{2-[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethanesulfinylmethyl]-phenyl}-3,4-dichloro-benzenesulfonamide

Compound I wherein Ar is 3,4-DiClPh, X is SO₂NH, q is 1, substitution inortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred solution of compound 19 (1 g; 3.1 mmol) in CH₂Cl₂ (30 mL),pyridine (0.5 mL; 6.2 mmol) and 3,4-Dichlorobenzenesulfonylchloride(0.48 mL; 3.1 mmol) were added. The reaction mixture was stirred fortwelve hours and then, methylene chloride (200 mL) were added into it.The resulting mixture was washed with an aqueous hydrochloric acidsolution 1N (1×150 mL) and evaporated. The resulting residue waspurified by column chromatography (eluent: methylenechloride/methanol9/1) to generate Example 130 as a white powder.

Yield: 91% (1.5 g; 2.8 mmol).

R_(f)=0.46 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 10.1 (s, 1H), 7.85 (broad d, 2H), 7.70 (broad d,1H), 7.40-7.30 (m, 3H), 7.00 (broad m, 1H), 4.30 (d, 1H), 4.20-4.00(broad m, 3H), 3.60-3.40 (broad, 8H), 2.0 (s, 3H).

MS: 554 (M+Na).

Examples 131 through 133 were prepared following the same multistepgeneral method as described for Example 130 utilizing the appropriatesubstituted amine —NR¹²R¹³ and the appropriate sulfonylchloride in step4. The analytical data is presented by each compounds molecular formulaand masse spectrum (M+H) or (M+Na) as shown in the following Table 4:TABLE 4 Example N^(o) Molecular Formula Peak Mass 131 C₂₁H₂₄FN₃O₅S₂ M +Na 504 132 C₂ ₁H₂₄ClN₃O₅S₂ M−1(ESI−) 496 133 C₂ ₁H₂₃Cl₂N₃O₅S₂ M + Na 554

Example 1341-(4-acetyl-piperazin-1-yl)-2-[2-(4-methoxy-phenylamino)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 4-OCH₃Ph, X is NH, q is 1, substitution inortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred mixture of 4-methoxyphenyl boronic acid (1 g; 6.6 mmol),myristic acid (0.3 g; 1.3 mmol) and copper(II) acetate anhydrous (0.12g; 0.66 mmol) in CH₂Cl₂ (10 mL) were added compound 19 (1.4 g; 4.3 mmol)in CH₂Cl₂ (10 mL) and 2,6-lutidine (0.52 mL; 4.5 mmol). The reactionmixture was stirred for two days. The catalyst was removed by filtrationon a pad of Celite, and the filtrate was evaporated. The resultingresidue was purified by column chromatography (eluent:methylenechloride/methanol 96/4) to generate Example 134 as a beigepowder.

Yield: 49 g; 2.1 mmol).

R_(f)=0.49 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 7.70 (s, 1H), 7.20-7.10 (m, 2H), 7.05 (broad d, 1H),6.90 (broad d, 2H), 6.85-6.70 (m, 3H), 4.30 (broad dd, 1H), 4.20 (broadd, 1H), 4.05 (broad m, 2H), 3.50 (broad, 8H), 2.00 (s, 3H).

MS: 452 (M+Na).

Examples 135 trough 141 were prepared following the same multistepgeneral method as desribed for Example 134 utilizing the appropriatesubstituted amine —NR¹²R¹³ and the appropriate substituted boronic acidin step 4. The analytical data is presented by each compounds molecularformula and masse spectrum (M+H) or (M+Na) as shown in the followingTable 5. TABLE 5 Example N^(o) Molecular Formula Peak Mass 135C₂₁H₂₅N₃O₃S M + Na 422 136 C₂₁H₂₅N₃O₃S M + Na 422 137 C₂₂H₂₇N₃O₄S M + Na452 138 C₂₁H₂₄FN₃O₃S M + Na 440 139 C₂₁H₂₄ClN₃O₃S M + Na 456 140C₂₁H₂₄FN₃O₃S M + Na 440 141 C₂₁H₂₃Cl₂N₃O₃S M + Na 490

Example 142 Thiophene-2-carboxylic acid{2-[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethanesulfinylmethyl]-phenyl}-amide

Compound I wherein Ar is 2-Thienyl, X is CONH, q is 1, substitution inortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred solution of compound 19 (1 g; 3.1 mmol) in CH₂Cl₂ (30 mL),pyridine (0.5 mL; 6.2 mmol) and 2-thiophenecarbonyl chloride (0.46 g;3.1 mmol) were added. The reaction mixture was stirred for twelve hoursand then, methylene chloride (100 mL) were added into it. The resultingmixture was washed with an aqueous hydrochloric acid solution 1N (2×100mL) and evaporated. The resulting residue was purified by columnchromatography (eluent: methylenechloride/methanol 9/1) to generateExample 142 as a white powder.

Yield: 86% (1.16 g; 2.7 mmol).

R_(f)=0.50 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 10.55 (s, 1H), 7.80 (broad d, 2H), 7.75 (broad d,1H), 7.45-7.30 (m, 2H), 7.25-7.15 (m, 2H), 4.45 (broad, 2H), 4.20-4.00(broad m, 2H), 3.50-3.40 (broad, 8H), 2.0 (s, 3H).

MS: 456 (M+Na).

Example 143 was prepared following the same multistep general method asdescribed for Example 142 utilizing the appropriate substituted amine—NR¹²R¹³ and the appropriate carbonyl chloride in step 4. The molecularformula and masse spectrum (M+H) or (M+Na) are presented for Example 143in Table 6. TABLE 6 Example N^(o) Molecular Formula Peak Mass 143C₂₀H₂₃N₃O₅S M + Na 440

Example 1441-(4-acetyl-piperazin-1-yl)-2-{2-[(thiophen-2-ylmethyl)-amino]-phenylmethanesulfinyl}-ethanone

Compound I wherein Ar is 2-Thienyl, X is CH₂NH, q is 1, substitution inortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a cooled solution of compound 19 (0.65 g; 2 mmol) in1,2-dichloroethane (10 mL), 2-thiophene carboxaldehyde (0.29 g; 2.6mmol), sodium triacetoxy borohydride (0.57 g; 2.7 mmol) and acetic acid(0.15 mL) were added. The reaction mixture was stirred under nitrogenfor three hours and then, ethylacetate (100 mL) were added into it. Theresulting mixture was washed with an aqueous sodium hydrogenocarbonate(1×100 mL), aqueous solution (1×100 mL) and evaporated. The resultingresidue was purified by column chromatography (eluent:methylenechloride/methanol 9/1) to generate Example 144 as a whitepowder.

Yield: 71% (0.6 g; 1.4 mmol).

R_(f)=0.45 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 7.40 (broad d, 1H), 7.20-7.00 (m, 3H), 6.85-6.95(broad m, 1H), 6.7-6.6 (broad m, 2H), 6.30 (broad, 1H), 4.50 (broad d,1H), 4.30 (broad d, 1H), 4.20-4.00 (broad m, 3H), 3.55-3.45 (broad, 8H),2.00 (s, 3H).

MS: 442 (M+Na).

Example 145 was prepared following the same multistep general method asdescribed for Example 144 utilizing the appropriate substituted amine—NR¹² R¹³ and the appropriate aldehyde in step 4. The molecular formulaand masse spectrum (M+H) or (M+Na) is presented for Example 145 in Table7. TABLE 7 Example N^(o) Molecular Formula Peak Mass 145 C₂₀H₂₅N₃O₄S M +Na 426

Example 1461-(4-acetyl-piperazin-1-yl)-2-[2-(3,4-dichloro-benzylamino)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 3,4-DiClPh, X is CH₂NH, q is 1, substitution inortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred solution of compound 19 (1 g; 3.1 mmol) in DMF (25 mL),diisopropylethylamine (0.6 mL; 3.4 mmol) and 3,4-dichlorobenzyl bromide(0.74 g; 3.1 mmol) were added. The reaction mixture was stirred fortwelve hours and then, ethylacetate (250 mL) were added into it. Theresulting mixture was washed with brine (2×200 mL) and evaporated. Theresulting residue was purified by column chromatography (eluent:methylenechloride/ methanol 9/1) to generate Example 146 as a whitepowder.

Yield: 51% (0.76 g; 1.6 mmol).

R_(f)=0.47 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 7.70 (broad s, 1H), 7.60 (broad d, 1H), (broad m,1H), 7.4 (broad d, 1H), 7.10 (broad m, 2H), 6.6 (broad t, 1H), 6.5(broad d, 1H), 6.3 (broad m, 1H), 4.4-4.3 (broad m, 3H), 4.2-4.0 (broad,3H), 3.55-3.35 (broad, 8H), 2.0 (s, 3H).

MS: 504 (M+Na).

Examples 147 through 149 were prepared following the same multistepgeneral method as described for Example 146 utilizing the appropriatesubstituted amine —NR¹²R¹³ and the appropriate benzyl halide in step 4.The molecular formula and masse spectrum (M+H) or (M+Na) are presentedfor each Examples in Table 8. TABLE 8 Example N^(o) Molecular FormulaPeak Mass 147 C₂₂H₂₆FN₃O₃S M + Na 454 148 C₂₂H₂₅Cl₂N₃O₃S M + Na 504 149C₂₂H₂₆FN₃O₃S M + Na 454

Example 149a

Compound I wherein Ar is 3,4-DiClPhenyl, X is CONH, q is 1, substitutionin para position, R² and R³ are H, Y—R¹ is CH₂ CO NH₂.

To a stirred solution of compound 19a (0.7 g; 3.3 mmol) in CH₂Cl₂ (30mL) were added pyridine (0.53 mL; 6.6 mmol) and3,4-dichlorobenzoylchloride (0.69 g; 3.3 mmol). The reaction mixture wasstirred for eight days and filtered. The resulting solid was washed withwater, ethyl acetate and ethanol, then dried under vacuum to giveExample 149a as a yellow solid.

Yield: 59% (0.75 g; 1.9 mmol).

¹H-NMR (DMSO-d₆) δ: 10.5 (s, 1H), 8.25 (broad s, 1H), 7.9 (broad d, 1H),7.8 (broad d, 1H), 7.75 (broad d, 2H), 7.7 (broad s, 1H), 7.3 (broad m,3H), 4.25 (d, 1H), 4.0 (d, 1H), 3.6 (d, 1H), 3.45 (d, 1H).

MS:407 (M+Na).

III—Compounds Prepared According to Scheme D.

Examples 150 to 153 were synthesized according to Scheme D.

A—Preparation of Compound I

Example 150

Compound I wherein Ar is Ph, X is OCH₂, q is 0, substitution in orthoposition, R² and R³ are H, Y—R¹ is CH₂COOMe.

A mixture of α,α′-dibromo-o-xylene (7.15 g, 27.1 mmol), methyl glycolate(2.87 g, 27.1 mmol) and K₂CO₃ (8.25 g, 59 mmol) in DMF (dry, 20 mL) wasstirred under argon at room temperature for 4 h. Phenol (2.54 g, 27mmol) was added to the reaction mixture and stirring was continuedovernight. The reaction mixture was filtered and the residue was washedseveral times with EtOAc. Combined filtrate and washings were washedsuccessively with 0.5N NaOH, water (twice) and brine, dried (magnesiumsulfate), and concentrated to generate a crude product. It was purifiedby flash chromatography (eluent:hexane/ethyl acetate 85/15) to generateexample 150 as a viscous oil.

Yield=18% (1.48 g; 4.9 mmol).

¹H-NMR (CDCl₃): δ7.74-6.81 (a series of m, 9H), 5.20 (s, 2H), 3.96 (s,2H), 3.66 (s, 3H), 3.31 (s, 2H).

MS: m/e 325 (M+Na).

Example 151

Compound I wherein Ar is Ph, X is OCH₂, q is 0, substitution in orthoposition, R² and R³ are H, Y—R¹ is CH₂COOH.

A mixture of Example 150 (1.48 g, 4.9 mmol), 1N NaOH (25 mL) andmethanol (25 mL) was kept under reflux for 4 h (the mixture becamehomogenous), cooled, concentrated, and diluted with water. It was thenneutralized with conc. HCl. and extracted into ethyl acetate (twice).Combined organic layer was washed with water and brine, dried (MgSO₄)and concentrated to generate Example 151 as a viscous oil that wasdirectly used in the next step.

Yield=88% (1.25 g; 4.34 mmol).

¹H-NMR (CDCl₃): δ7.82-6.80 (a series of m, 9H), 5.20 (s, 2H), 3.98 (s,2H), 3.14 (s, 2H).

Example 152

Compound I wherein Ar is Ph, X is OCH₂, q is 0, substitution in orthoposition, R² and R³ are H, Y—R¹ is CH₂COONH₂.

A mixture of Example 151 (1.25 g, 4.34 mmol), HOBt.NH₃ complex (1.45 g,9.53 mmol), TBTU (1.70 g, 5.29 mmol) in DMF (15 mL) was stirred at roomtemperature overnight. It was then diluted with dichloromethane andsuccessively washed with water, 2% citric acid, water, 2% NaHCO₃, waterand brine, dried (MgSO₄), and concentrated to generate a crude product.It was purified by flash chromatography (eluent:hexane/ethyl acetate1/4) to generate Example 152.

Yield=67% (0.83 g; 2.89 mmol).

¹H-NMR (CDCl₃): δ7.74-6.96 (a series of m, 9H), 6.52 (br s, 1H), 5.39(br s, 1H), 5.16 (s, 2H), 3.89 (s, 2H), 3.14 (s, 2H).

Example 153 2-(2-phenoxymethyl-phenylmethanesulfinyl)-acetamide

Compound I wherein Ar is Ph, X is OCH₂, q is 1, substitution in orthoposition, R² and R³ are H, Y—R¹ is CH₂COONH₂.

To a solution of Example 152 (0.82 g, 2.87 mmol) in acetic acid (10 mL)was added hydrogen peroxide (50% in water, 200 μL). The reaction mixturewas stirred at room temperature for 4 h, neutralized (carefully) withaq. NaHCO₃ solution and extracted into ethyl acetate (twice). Combinedorganic layer was washed with brine, dried (MgSO₄) and concentrated togive a crude product that was purified by flash chromatography (eluentdichloromethane/MeOH 93/7) to generate Example 153.

Yield=70% (0.61 g; 2.01 mmol).

m.p.: 153-154 ° C.

¹H-NMR (DMSO-d₆): δ7.71 (s, 1H), 7.52(s, 1H), 7.37-6.93 (a series of m,9H), 5.21 (s, 2H), 4.39 (d, 1H), 4.17(d, 1H), 3.77 (d, 1H), 3.55 (d,1H).

MS: 326 (M +Na),

BIOLOGICAL DATA Methodology: Evaluation of Wake Promoting Activity inRats

The methodology utilized for evaluating wake promoting activity of testcompounds is based on that described by Edgar and Seidel, Journal ofPharmacology and Experimental Therapeutics, 283:757-769, 1997, andincorporated herein in its entirety by reference.

Animal Surgery. Adult, male Wistar rats (275-320 g from Charles RiverLaboratories, Wilmington, Mass.) were anesthetized (Nembutal, 45 mg/kg,ip.) and surgically prepared with implants for recording of chronic EEG(encephalographic) and EMG (electromyographic) recording. The EEGimplants were made from commercially available components (Plastics One,Roanoke, Va.). EEG signals were recorded from stainless steel screwelectrodes: 2 frontal (+3.0 mm AP from bregma, ±2.0 mm ML), and 2occipital (−4.0 mm AP from bregma, ±2.0 mm ML). Two Teflon-coatedstainless steel wires were positioned under the nuchal trapezoid musclesfor EMG recording. All electrode leads were inserted into a connectorpedestal and the pedestal affixed to the skull by application dentalacrylic. Antibiotic was administered post surgically and antibioticcream was applied to the wound edges to prevent infection. At least oneweek elapsed between surgery and recording.

Recording environment. Postsurgically, rats were housed in pairs in anisolated room. Food and water were available ad libitum, ambienttemperature was 21° C., and humidity was 55%. At least 24 hrs prior torecording, they were placed in Nalgene containers (31×31×31 cm) with awire-grid top, and entry to the room was prohibited during the day ofrecording except for dosing. The containers were placed on a rack withtwo shelves, 4 containers per shelf. Fluorescent overhead room lightswere set to a 24 hr. light/dark cycle (on at 7 AM, off at 7 PM). Lightlevels inside the containers were 38 and 25 lux for the top and bottomshelves respectively. Background white-noise (68 db inside thecontainers) was present in the room to mask ambient sounds.

Data acquisition. EEG and EMG signals were led via cables to acommutator (Plastics One) and then to pre-amplifiers (model 1700, A-MSystems, Carlsborg, Wash.). EEG and EMG signals were amplified (10K and1K respectively) and bandpass filtered between 0.3 and 500 Hz for EEGand between 10 and 500 Hz for EMG. These signals were digitized at 128samples per second using ICELUS sleep research software (M. Opp, U.Texas; see Opp, Physiology and Behavior 63:67-74, 1998, and Imeri,Mancia, and Opp, Neuroscience 92:745-749, 1999, incorporated byreference herein in their entirety) running under Labview 5.1 softwareand data acquisition hardware (PCI-MIO-16E-4; National Instruments,Austin, Tex.). On the day of dosing, data was recorded for 6 to 10 hoursbeginning at 11 AM.

Drug administration and study design. Compounds were evaluated on groupsof from 4 to 8 rats carried out over one or two separate test sessions.Each animal was tested with a different compound or vehicle for up to 10weeks with at least 7 days between successive tests. A vehicle group wasincluded in all experiments, and each animal received vehicle every4^(th) test. Test compounds were suspended in sterile 0.25%methylcellulose (pH=6.2; Upjohn Co., Kalamazoo, Mich.) at 30 mg/mL.Although compounds can be administered at dosages greater than 100 mg/kgand are expected to be active under the selection criteria of dataanalysis, unless otherwise noted, compounds were administered at asingle dose of 100 mg/kg. Dosing was carried out at noon, while the ratswere predominantly asleep. Each rat was lifted out of its container,given an intraperitoneal injection in a volume of 5 mL/kg, and replaced.Dosing required approximately 30 sec per rat.

Sleep/wake scoring. Sleep and wake activity were determined manuallyusing ICELUS software. This program displays the EEG and EMG data inblocks of 6 sec along with the EEG frequency spectrum. Arousal state wasscored as awake, rapid eye-movement (REM), or slow-wave or non-REM sleep(NREM) according to visual analysis of EEG frequency and amplitudecharacteristics and EMG activity (Opp and Krueger, 1994; Van Gelder, etal., 1991; Edgar, et al., 1991, 1997; Seidel, et al, 1995, incorporatedby reference herein in their entirety). Essentially, waking activityconsists of relatively low-amplitude EEG activity with relatively lowerpower in the frequency band from 0.5-6 Hz, accompanied by moderate tohigh level EMG activity. In a particular waking state (“theta-waking”),EEG power can be relatively focused in the 6-9 Hz (theta) range, butsignificant EMG activity is always present. NREM sleep is characterizedby relative high-amplitude EEG activity with relatively greater power inthe low frequency band from 0.5-6 Hz, accompanied by little or no EMGactivity. REM sleep is characterized by moderate and constant amplitudeEEG focused in the theta (6-9 Hz) range, similar to waking theta, butwith no EMG activity.

Data analysis and statistics. Two basic outcome measures were used toascertain whether a compound exhibited wake-enhancing activity. Thefirst was the percent time spent awake for each 30 min period followingdosing. The second was the total time spent awake in the first 3 hrsfollowing dosing (3 hr AUC; maximum 180 min). For purposes ofascertaining activity of a test compound, wake activity values werecompared against corresponding vehicle values. The vehicle values wereof two types. The first type was the corresponding within-experimentvehicle, that is, a value for the vehicle group run concurrently withthe test compound. A second “reference” vehicle value consisted of themean 3 hr AUC value calculated from 234 animals in 59 separateexperiments carried out during the same time period as the evaluationsof the test compounds (mean ±SD =69.22±20.12; 95% confidencelimits=66.63-71.81). Two-tailed, unpaired t-tests were performed on thewake time values for drug versus vehicle treated animals, and compoundswith p≦0.05 were deemed significantly wake-promoting. A test compoundwas considered “active” if it met one of the following three criteria.

-   -   (i) The 3 hr AUC value for the test compound was significantly        greater (p≦0.05) than the mean wake value for the reference        vehicle group (N=234).    -   (ii) The 3 hr AUC value for the test compound was significantly        greater (p≦0.05) than the corresponding value for the vehicle        group within the same experiment.    -   (iii) One or more of the half-hour wake time values from 0.5 to        2 hrs after dosing was significantly greater (p≦0.05) in the        test compound group than in the corresponding vehicle group        within the same experiment.

Results

Compounds of the invention either have demonstrated or are expected todemonstrate utility for wake promoting activity.

As example, the three-hours AUC value (mean±sem) for the referencevehicle group and for the test compounds are reported Table 9 forExamples 22, 40 and 113. These test compounds were administered by i.p.route at a 100 mg/kg dose and the time-course of the percent of timeawake as function of time was estimated from 1 hr prior to 5 hours postdosing. TABLE 9 Mean AUC_(0-3h) values (± sem) for the reference vehiclegroup and for test compounds Vehicle Test compound Mean sem Mean sem pExample 22 67.1 5.3 162.7 6.5 0.000 Example 40 66.9 5.5 118.9 10.6 0.001Example 113 63.5 9.1 99.0 10.4 0.022AUC_(0-3h) (% of waiking time × hr) − n = 8 Rats per test compound and 8rats per control groups.

As compared to the control groups, compounds of Example 22, 40 and 113produced a significantly greated wakefulness than that observed in thevehicle-treated animals (p<0.05).

References

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated in their entirety herein by reference:

Touret, et al., Neuroscience Letters, 189:43-46, 1995.

Van Gelder, R. N. et al., Sleep 14:48-55, 1991.

Edgar, D. M., J. Pharmacol. Exp. Ther. 282:420-429, 1997.

Edgar and Seidel, J. Pharmacol. Exp. Ther., 283:757-69, 1997.

Hernant et al., Psychopharmacology, 103:28-32, 1991.

Lin et al., Brain Research, 591:319-326, 1992.

Opp and Krueger, American Journal of Physiology 266:R688-95, 1994

Panckeri et al., Sleep, 19(8):626-631, 1996.

Seidel, W. F., et al., J. Pharmacol. Exp. Ther. 275:263-273, 1995.

Shelton et al., Sleep 18(10):817-826, 1995.

Welsh, D. K., et al., Physiol. Behav. 35:533-538, 1985.

Utility

The present invention provides a method of treating diseases andconditions in a subject in need thereof comprising administering to saidsubject a therapeutically effective amount of a compound of formula (I).For example, the compounds of of the present invention are use in thetreatment of diseases, including treatment of sleepiness, promotion ofwakefulness, treatment of Parkinson's disease, cerebral ischemia,stroke, sleep apneas, eating disorders, stimulation of appetite andweight gain, treatment of attention deficit hyperactivity disorder(“ADHD”), enhancing function in disorders associated withhypofunctionality of the cerebral cortex, including, but not limited to,depression, schizophrenia, fatigue, in particular, fatigue associatedwith neurologic disease, such as multiple sclerosis, chronic fatiguesyndrome, and improvement of cognitive dysfunction.

Dosage and Formulation

The compounds of the present invention can be administered fortherapeutic purposes by any means that results in the contact of theactive agent with the agent's site of action in a subject. The compoundsmay be administered by any conventional means available for use inconjunction with pharmaceuticals, either as individual therapeuticagents or in a combination with other therapeutic agents, such as, forexample, analgesics, or in combination with antidepressants, includingbut are not limited to tricyclic antidepressants (“TCAs”), SelectiveSerotonin Reuptake Inhibitors (“SSRIs”), Serotonin and NoradrenalineReuptake Inhibitors (“SNRIs”), Dopamine Reuptake Inhibitors (“DRIs”),Noradrenaline Reuptake Inhibitors (“NRUs”), Dopamine, Serotonin andNoradrenaline Reuptake Inhibitors (“DSNRIs”) and Monoamine OxidaseInhibitors (“MAOIs) including reversible inhibitors of monoamine oxidasetype A (RIMAs). The compounds of the present invention are preferablyadministered in therapeutically effective amounts for the treatment ofthe diseases and disorders described herein.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques. The effective dose will vary depending upon anumber of factors, including the pharmacodynamics of the active agent,the type and extent of progression of the disease or disorder, the age,weight and health of the particular patient, the formulation of theactive and its mode and frequency of administration, and the desiredeffect with a minimization of side effects. Typically, the compounds areadministered at lower dosage levels, with a gradual increase until thedesired effect is achieved.

Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of bodyweight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kgof body weight per day. A typical daily dose for adult humans can rangefrom about 1 to about 1000 mg of the active agent, particularly fromabout 1 to about 400 mg, and including 25, 50, 85, 100, 150, 170, 200,255, 250, 255, 340, 400, 425, 500, 600, 700, 750, 800, and 900 mg doses,and equivalent doses for a human child.

The compounds may be administered in one or more unit dose forms, andthey may be administered in a single daily dose or in two, three or fourdoses per day. The unit dose ranges from about 1 to about 1000 mg,particlularly from about 1 to about 400 mg, and including 25, 50, 85,100, 150, 170, 200, 255, 250, 255, 340, 400, 425, 500, 600, 700, 750,800, and 900 mg unit doses, and equivalent unit doses for a human child.In particular, the unit dosages range from about 1 to about 500 mgadministered one to four times a day, preferably from about 10 mg toabout 300 mg, two times a day. In an alternate method of describing aneffective dose, an oral unit dose is one that is necessary to achieve ablood serum level of about 0.05 to 20 μg/ml in a subject, and preferablyabout 1 to 20 μg/ml.

The compounds of the present invention may be formulated intopharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. The active agent may be presentin about 0.5-95% by weight of the composition. The excipients areselected on the basis of the chosen route of administration and standardpharmaceutical practice, as described, for example, in Remington: TheScience and Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.

The compositions can be prepared for administration by oral means,including tablets, pills, powders, capsules, troches and the like;parenteral means, including intravenous, intramuscular, and subcutaneousmeans; topical or transdermal means, including patches, creams,ointments, lotions, pastes, gels, solutions, suspensions, aerosols, andpowders and the like; transmucosal means, including nasal, rectal,vaginal, sublingual and buccal means; ophthalmic or inhalation means.Preferably the compositions are prepared for oral administration,particularly in the form of tablets, capsules or syrups; parenteraladministration, particularly in the form of liquid solutions,suspensions or emulsions; intranasal administration, particularly in theform of powders, nasal drops, or aerosols; or for topical use, such aspatches, creams, ointments, and lotions.

For oral administration, the tablets, pills, powders, capsules, trochesand the like can contain one or more of the following: diluents orfillers such as starch, or cellulose; binders such as microcrystallinecellulose, gelatins, or polyvinylpyrrolidone; disintegrants such asstarch or cellulose derivatives; lubricants such as talc or magnesiumstearate; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin; and flavoring agents such as peppermint orcherry flavoring. Capsules may contain any of the above ingredients, andmay also contain a semi-solid or liquid carrier, such as a polyethyleneglycol. The solid oral dosage forms may have coatings of sugar, shellac,or enteric agents. Liquid preparations may be in the form of aqueous oroily suspensions, solutions, emulsions, syrups, elixirs, etc., or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as surfactants, suspending agents,emulsifying agents, diluents, sweetening and flavoring agents, dyes andpreservatives.

The compositions may also be administered parenterally. Thepharmaceutical forms acceptable for injectable use include, for example,sterile aqueous solutions, or suspensions. Aqueous carriers includemixtures of alcohols and water, buffered media, and the like. Nonaqueoussolvents include alcohols and glycols, such as ethanol, and polyethyleneglycols; oils, such as vegetable oils; fatty acids and fatty acidesters, and the like. Other components can be added includingsurfactants; such as hydroxypropylcellulose; isotonic agents, such assodium chloride; fluid and nutrient replenishers; electrolytereplenishers; agents which control the release of the active compounds,such as aluminum monostearate, and various co-polymers; antibacterialagents, such as chlorobutanol, or phenol; buffers; suspending agents;thickening agents; and the like. The parenteral preparations can beenclosed in ampules, disposable syringes or multiple dose vials. Otherpotentially useful parenteral delivery systems for the active compoundsinclude ethylene-vinyl acetate copolymer particles, osmotic pumps,implantable infusion systems, and liposomes.

Other possible modes of administration include formulations forinhalation, which include such means as dry powder, aerosol, or drops.They may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for topical use are in the form ofan ointment, cream, or gel. Typically these forms include a carrier,such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, ortheir combinations, and either an emulsifying agent, such as sodiumlauryl sulfate, or a gelling agent, such as tragacanth. Formulationssuitable for transdermal administration can be presented as discretepatches, as in a reservoir or microreservoir system, adhesivediffusion-controlled system or a matrix dispersion-type system.Formulations for buccal administration include, for example lozenges orpastilles and may also include a flavored base, such as sucrose oracacia, and other excipients such as glycocholate. Formulations suitablefor rectal administration are preferably presented as unit-dosesuppositories, with a solid based carrier, such as cocoa butter, and mayinclude a salicylate.

The compositions of the present invention may be formulated to controland/or delay the release of the active agent(s). Such controlled-,delayed, sustained-, or extended-release compositions are well-known inthe art, and may include, for example, reservoir or matrix diffusionproducts, as well as dissolution systems. Some compositions may utilize,for example biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers as excipients.

Preferred embodiments of the invention include the following:

1. A compound of formula (A):

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, OR²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,            C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered            heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,            arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴ ,            NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and            S(O)_(y)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂CO, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,        C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C;    -   Y is C₁-C₆ alkylene; or        -   (C₁-C₄ alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;    -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10        membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered        heterocycloalkylene; wherein said arylene, heteroarylene,        cycloalkylene, and heterocycloalkylene groups are optionally        substituted with one to three R²⁰ groups;    -   R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,        OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,        NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;        -   wherein said aryl groups are optionally substituted with one            to three R²⁰ groups;    -   R² and R³ are each independently selected from from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered        heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,        NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said        alkyl and aryl groups are optionally substituted with one to        three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H, C₃-C₇        alkyl and C₆-C₁₀ aryl;        -   wherein said alkyl and aryl group are optionally substituted            with one to three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen        to which they are attached, form a 3-7 membered heterocyclic        ring;        -   wherein said alkyl group and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl;        -   wherein said alkyl, aryl and arylalkyl groups are optionally            substituted with one to three R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl        optionally substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl,        phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²²,        OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,        OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and        C₁-C₆ alkyl;    -   R²² at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   m is 0 or 1;    -   n is 0 or 1;    -   q is 0, 1, or 2;    -   y is 0, 1, or 2;    -   with the exclusion of the compounds wherein:        -   Y is C₂ alkylene substituted with one to three C₁-C₆            alkylene and/or NR²³R²⁴ and/or NR²¹CO₂R²²; and        -   R¹ is C(═O)NR¹²R¹³.            and with the exclusion of the compound:    -   tetrahydro-2-[[{4-(phenylthio)phenyl]methyl}thio]acetyl]-2H-1,2-oxazine;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

2. The compound according to claim 1, wherein:

-   -   Y is C₁-C₆alkylene;    -   (C₁-C₄ alkylene)_(m)—Z¹—(C₁-C₄ alkylene)_(n);    -   C₁-C₄ alkylene-Z²—C₁-C₄ alkylene;    -   wherein said alkylene groups are optionally substituted with one        to three R²⁰ groups;    -   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered        heteroarylene,    -   C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene;        wherein said arylene, heteroarylene, cycloalkylene, and        heterocycloalkylene groups are optionally substituted with one        to three R²⁰ groups;    -   Z² is O, NR^(10A), or S(O)_(y).

3. The compound according to any of claims 1 or 2 wherein q is 1.

4. The compound according to any of claims 1 to 3 wherein R¹ is H.

5. The compound according to any of claims 1 to 3 wherein R¹ is selectedfrom NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, andNR²¹S(O)₂NR¹²R¹³.

6. The compound according to claim 5 wherein R¹ is selected fromNR¹²R¹³; NR²¹C(═O)R¹⁴; C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³; andNR²¹C(═O)NR¹²R¹³.

7. The compound according to claim 6 wherein R¹ is C(═O)NR¹²R¹³.

8. The compound according to any of the claims 5 to 7 wherein R¹² andR¹³ are each independently selected from H and C₁-C₆ alkyl.

9. The compound according to any of the claims 5 to 7 wherein R¹² andR¹³ together with the nitrogen to which they are attached, form a 3-7membered heterocyclic ring, wherein said heterocyclic ring is optionallysubstituted with one R²⁰ group.

10. The compound according to claim 5 wherein R¹ is selected fromC(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,and NR²¹S(O)₂NR¹²R¹³.

11. The compound according to claims 1 to 10 wherein X is O, S(O)_(y),N(R¹⁰).

12. The compound according to claims 1 to 10 wherein X is OC(R²²)₂,C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²²,NR²²S(O)₂, C(R²²)₂C(R²²)₂.

13. The compound according to claim 12 wherein X is OC(R²²)₂,C(R²²)₂NR²¹, C(═O)N(R²¹), S(O)₂—NR²².

14. The compound according to any of claims 1 to 13 wherein Y is C₁-C₆alkylene.

15. The compound according to claim 14 wherein Y is CH₂.

16. The compound according to any of claims 2 to 13 wherein Y is (C₁-C₄alkylene)_(m)—Z¹—(C₁-C₄ alkylene)_(n).

17. The compound according to claim 16 wherein Z¹ is C₆-C₁₀ arylene orC₃-C₆ cycloalkylene.

18. The compound according to claim 17 wherein Z¹ is phenylene.

19. The compound according to claim 16 wherein Z¹ is 5-10 memberedheteroarylene or 3-6 membered heterocycloalkylene.

20. The compound according to claim 16 wherein Z¹ is CR²¹=CR²¹ or C≡C.

21. The compound according to any of claims 2 to 13 wherein Y is C₁-C₄alkylene-Z²—C₁-C₄ alkylene.

22. The compound according to claim 21 wherein Z² is O.

23. The compound according to claims 1 or 2 with the structure:

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, OR²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, C₁-C₆ alkyl, phenyl, arylalkyl, and            C(═O)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂;    -   Y is C₁-C₆ alkylene;        -   C₁-C₄ alkylene-Z¹—(C₁-C₄ alkylene)_(n); or        -   C₁-C₄ alkylene-Z²—C₁-C₄ alkylene;        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;    -   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered        heteroarylene,        -   C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene;    -   Z² is O, NR^(10A), or S(O)_(y);    -   R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,        C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,        NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;    -   R² and R³ are each independently selected from F, Cl, Br, I,        OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5        or 6 membered heteroaryl, arylalkyl, C(═O)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C(═O)R¹⁴, and S(O)_(y)R¹⁴;        -   wherein said alkyl groups are optionally substituted with            one to three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H or C₃-C₇        alkyl, wherein said alkyl group is optionally substituted with        one to three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H, and C₁-C₆ alkyl, or R¹² and R¹³, together with the        nitrogen to which they are attached, form a 3-7 membered        heterocyclic ring;        -   wherein said alkyl group and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl;        -   wherein said alkyl, aryl and arylalkyl groups are optionally            substituted with one to three R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, phenyl, benzyl,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,        NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and        C₁-C₆ alkyl;    -   R²² at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, and C₁-C₆ alkyl, or R²³ and R²⁴, together with the        nitrogen to which they are attached, form a 3-7 membered        heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   n is 0 or 1;    -   y is 0, 1, or 2;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof.

24. The compound according to claim 23 wherein:

-   -   Y is C₁-C₆ alkylene, C₁-C₄ alkylene-Z¹—C₁-C₄ alkylene, or C₁-C₄        alkylene-Z²—C₁-C₄ alkylene, wherein said alkylene groups are        optionally substituted with one to three C₁-C₆ alkyl groups;        -   Z¹ is CR²¹═CR²¹, C≡C, or phenyl;        -   Z² is O, NR^(10A), or S(O)_(y);    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂; and    -   R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,        and C(═O)NR¹²R¹³.

25. The compound according to claim 24 wherein R¹ is C(═O)NR¹²R¹³.

26. The compound according to claim 25 having the structure of formula(Ib):

27. The compound according to claim 26 wherein X is O, S(O)_(y), N(R¹⁰),OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O),S(O)₂—NR²², NR²²S(O)₂.

28. The compound according to claim 27 wherein X is O, S(O)_(y), NH.

29. The compound according to claim 27 wherein X is OCH₂, CH₂O, CH₂NH,NHCH₂, C(═O)NH, NHC(═O), S(O)₂NH, NHS(O)₂.

30. The compound according to any of claims 27 wherein X is NH, O—CH₂,CH₂NH, C(═O)NH, S(O)₂—NH.

31. The compound according to any of claims 1 to 30 wherein R² and R³are each independently selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5 or 6 membered heteroaryl,arylalkyl, C(═O)R²².

32. The compound according to any of claims 26 to 31 wherein Y is C₁-C₆alkylene.

33. The compound according to claim 32 wherein Y is CH₂.

34. The compound according to any of claims 26 to 31 wherein Y is (C₁-C₄alkylene)_(n)—Z¹—C₁-C₄ alkylene and Z¹ is phenyl, 5-6 memberedheteroarylene, CR²¹═CR²¹, or C≡C.

35. The compound according to claim 1 selected in accordance with thefollowing table, wherein: TABLE 1

Ex. n° Ar X Position* R² R³ q Y—R¹  13 3,4-DiClPh O para H H 0 CH₂CO-N-piperazinyl-N-Boc  14 3,4-DiClPh O para H H 0 CH₂CO-N-piperazinyl  193,4-DiClPh O para H H 1 CH₂CO-N-piperazinyl  16 4-ClPh S para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  23 4-ClPh S para H H 1CH₂CO-1-(4-acetyl)- piperazinyl  24 4-ClPh SO para H H 1CH₂CO-1-(4-acetyl)- piperazinyl  29 Ph O para H H 1 CH₂CONHCHMe₂ Ph Ometa H H 0 CH₂CO-N- pyrrolidinyl  31 Ph O meta H H 1 CH₂CO-N-pyrrolidinyl Ph O meta H H 0 CH₂CONH₂  32 Ph O meta H H 1 CH₂CONH₂ Ph Ometa H H 0 CH₂CONMe₂  33 Ph O meta H H 1 CH₂CONMe₂ Ph O meta H H 0CH₂CONHCHMe₂  34 Ph O meta H H 1 CH₂CONHCHMe₂ Ph O meta H H 0CH₂CO-1-(4-acetyl)- piperazinyl  35 Ph O meta H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 4-OCH₃Ph O para H H 0 CH₂CONH₂  36 4-OCH₃Ph O para H H 1CH₂CONH₂ 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  374-OCH₃Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para HH 0 CH₂CO-N-piperazinyl  38 4-OCH₃Ph O para H H 1 CH₂CO-N-piperazinyl3,4-DiClPh O para H H 0 CH₂CONH₂  39 3,4-DiClPh O para H H 1 CH₂CONH₂ 11 3,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  223,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl  27 3,4-DiClPh Opara H H 2 CH₂CO-1-(4-acetyl)- piperazinyl  30 3,4-DiClPh O para H H 1CH₂COOH  15 3,4-DiClPh O ortho H H 0 CH₂CONH₂  20 3,4-DiClPh O ortho H H1 CH₂CONH₂ 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  403,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh Opara H H 0 CH₂CO-1-(4- carboxamide)- piperazinyl  41 3,4-DiClPh O para HH 1 CH₂CO-1-(4- carboxamide)- piperazinyl 4-OCH₃Ph O ortho H H 0CH₂CONH₂  42 4-OCH₃Ph O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0CH₂CONH₂  43 2-ClPh O para H H 1 CH₂CONH₂ 4-OHPh O ortho H H 0 CH₂CONH₂ 44 4-OHPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho H H 0 CH₂CONH₂  452-ClPh O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  46 2-ClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-ClPh O para H H 0 CH₂CO-N-piperazinyl  47 2-ClPh O para H H 1CH₂CO-N-piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 48 4-FPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl  95 4-FPh O paraH H 2 CH₂CO-1-(4-acetyl)- piperazinyl  96 4-FPh O para H H 1 CH₂COOH4-FPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  49 4-FPh O ortho HH 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-FPh O para H H 0 CH₂CONH₂  504-FPh O para H H 1 CH₂CONH₂ 4-FPh O ortho H H 0 CH₂CONH₂  51 4-FPh Oortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CONH₂  52 2-Naphthyl Oortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  53 2-Naphthyl O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-Naphthyl O para H H 0 CH₂CONH₂  54 2-Naphthyl O para H H 1 CH₂CONH₂2-BiPh O para H H 0 CH₂CONH₂  55 2-BiPh O para H H 1 CH₂CONH₂ 2-BiPh Oortho H H 0 CH₂CONH₂  56 2-BiPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho HH 0 CH₂CO-1-(4-acetyl)- piperazinyl  57 2-ClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2-Naphthyl O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  58 2-Naphthyl O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2-BiPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  59 2-BiPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-BiPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  60 2-BiPh O para HH 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-ClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  61 4-ClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para H H 0CH₂CO-1-(4-methyl)- piperazinyl  62 4-OCH₃Ph O para H H 1CH₂CO-1-(4-methyl)- piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-1-(4-ethylcarboxylate)- piperazinyl  63 3,4-DiClPh O para H H 1 CH₂CO-1-(4-ethylcarboxylate)- HHpiperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-hydroxyethyl)- piperazinyl  64 4-FPh O para H H 1 CH₂CO-1-(4-hydroxyethyl)- piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-hydroxyethyl)- piperazinyl  65 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4-hydroxyethyl)- piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-methyl)-piperazinyl  66 4-FPh O para H H 1 CH₂CO-1-(4-methyl)- piperazinyl4-ClPh O para H H 0 CH₂CONH₂  67 4-ClPh O para H H 1 CH₂CONH₂ 4-FPh Opara H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  68 4-FPh O para HH 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-OCH₃Ph O para H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  69 4-OCH₃Ph O para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-ClPh S para H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  70 4-ClPh S para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  71 4-ClPh SO para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 3,4-DiClPh O ortho H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  72 3,4-DiClPh O ortho H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl Ph O ortho H H 0 CH₂CONH₂  97Ph O ortho H H 1 CH₂CONH₂ Ph O ortho H H 0 CH₂CO-N- pyrrolidinyl  98 PhO ortho H H 1 CH₂CO-N- pyrrolidinyl Ph O ortho H H 0 CH₂CONMe₂  99 Ph Oortho H H 1 CH₂CONMe₂ Ph O para H H 0 CH₂CONMe₂ 100 Ph O para H H 1CH₂CONMe₂ Ph O para H H 0 CH₂CO-N- pyrrolidinyl 101 Ph O para H H 1CH₂CO-N- pyrrolidinyl Ph O para H H 0 CH₂CONH₂ 102 Ph O para H H 1CH₂CONH₂ Ph O ortho H H 0 CH₂CONHCH₂CN 103 Ph O ortho H H 1 CH₂CONHCH₂CNPh O ortho H H 0 CH₂CONHCHMe₂ 104 Ph O ortho H H 1 CH₂CONHCHMe₂ Ph Oortho H H 0 CH₂CONHCMe₃ 105 Ph O ortho H H 1 CH₂CONHCMe₃ Ph O ortho H H0 CH₂CO-1-(4- hydroxy)-piperidinyl 106 Ph O ortho H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl  12 Ph O ortho H H 0 CH₂CONH(CH₂)₂OH  21 Ph O orthoH H 1 CH₂CONH(CH₂)₂OH Ph O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl107 Ph O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl Ph O meta H H 0CH₂CONH(CH₂)₂OH 108 Ph O meta H H 1 CH₂CONH(CH₂)₂OH Ph O meta H H 0CH₂CO-1-(4- hydroxy)-piperidinyl 109 Ph O meta H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl 110 Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl111 Ph O para H H 1 CH₂CONH(CH₂)₂OH 112 Ph O para H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl 113 4-ClPh CONH ortho H H 1 CH₂CONH₂ 1143,4-DiOCH₃Ph CONH ortho H H 1 CH₂CONH₂ 115 2-Naphthyl CONH ortho H H 1CH₂CONH₂ 116 4-ClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 1173,4DiFPh CONH ortho H H 1 CH₂CONH₂ 118 2,4-DiOCH₃Ph CONH ortho H H 1CH₂CONH₂ 119 3,4,5- CONH ortho H H 1 CH₂CONH₂ TriOCH₃Ph 120 3,4-DiOCH₃PhCONH meta H H 1 CH₂CONH₂ 121 2,4-DiOCH₃Ph CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 122 3,4-DiOCH₃Ph CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 123 4-FPh CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 124 3,4-DiClPh CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 125 2,4-DiOCH₃Ph CONH meta H H 1CH₂CONH₂ 126 4-FPh CONH meta H H 1 CH₂CONH₂ 127 3,4-DiClPh CONH meta H H1 CH₂CONH₂ 7 4-ClPh O para H H 0 CH₃ 8 4-ClPh O para H H 1 CH₃ 9 4-ClPhO para H H 1 CH₂[4(4- ClPhenoxy)phenyl] 3,4-DiClPh O para H H 0 CH₃  103,4-DiClPh O para H H 1 CH₃ 4-ClPh S ortho H H 0 CH₂CO-N-piperazinyl  734-ClPh S ortho H H 1 CH₂CO-N-piperazinyl 2,3-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  74 2,3-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  75 2,5-DiCiPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0 CH₂CONH₂  762,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,3-DiClPh O ortho H H 0 CH₂CONH₂  772,3-DiClPh O ortho H H 1 CH₂CONH₂ 2,4-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  78 2,4-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  79 2,4-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O para H H 0 CH₂CONH₂  802,4-DiClPh O para H H 1 CH₂CONH₂ 2,4-DiClPh O ortho H H 0 CH₂CONH₂  812,4-DiClPh O ortho H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  82 3,5-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  83 3,5-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0 CH₂CONH₂  843,5-DiClPh O para H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0 CH₂CONH₂  853,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,5-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  86 2,5-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh S para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  87 3,4-DiClPh S para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh S para H H 0 CH₂CONH₂  882,5-DiClPh S para H H 1 CH₂CONH₂ 3,4-DiClPh S para H H 0 CH₂CONH₂  893,4-DiClPh S para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  90 2,3-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  91 2,6-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0 CH₂CONH₂  922,6-DiClPh O para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0 CH₂CONH₂  932,3-DiClPh O para H H 1 CH₂CONH₂  94 2,3-DiClPh O para H H 2 CH₂CONH₂135 Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 136 Ph NH para H H1 CH₂CO-1-(4-acetyl)- piperazinyl 134 4-OCH₃Ph NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 131 4-FPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 137 4-OCH₃Ph NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 138 4-FPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 139 4-ClPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 140 4-FPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 128 3,4-DiClPh CONH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 129 4-FPh CONH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 141 3,4-DiClPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 132 4-ClPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 147 4-FPh CH₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 133 3,4-DiClPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 148 3,4-DiClPh CH₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 149 4-FPh CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 146 3,4-DiClPh CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 130 3,4-DiClPh SO₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 145 2-Furyl CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 144 2-Thienyl CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 142 2-Thienyl CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 143 2-Furyl CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 152 Ph OCH₂ ortho H H 0 CH₂CONH₂ 153 PhOCH₂ ortho H H 1 CH₂CONH₂  17 4-ClPh O para 2′-Cl H 0CH₂CO-1-(4-acetyl)- piperazinyl  18 4-ClPh O para 2′-Cl H 0 CH₂CONH₂  254-ClPh O para 2′-Cl H 1 CH₂CO-1-(4-acetyl)- piperazinyl  26 4-ClPh Opara 2′-Cl H 1 CH₂CONH₂ 149a 3,4-DiClPh CONH para H H 1 CH₂CONH₂ 109a4-ClPh O ortho H H 1 CH₂CONH₂ 109b 3-Cl-4-FPh O ortho H H 1 CH₂CONH₂109c 4-Cl-3-FPh O ortho H H 1 CH₂CONH₂ 109d 3-Cl-4-FPh O ortho H H 2CH₂CONH₂  10a 4-ClPh O ortho 4′-Cl H 0 CH₂COOH  18a 4-ClPh O ortho 4′-ClH 0 CH₂CONH₂  27a 4-ClPh O ortho 4′-Cl H 1 CH₂CONH₂  27b 4-ClPh O ortho4′-Cl H 2 CH₂CONH₂ 109e 3,4-DiFPh O ortho 4′-Cl H 1 CH₂CONH₂ 109f3,4-DiClPh O ortho H H 2 CH₂CONH₂  30a 3,4-DiClPh O ortho H H 1 CH₂COOH 30d 3,4-DiClPh O ortho H H 0 CH₂COOMenthyl (1R,2S,5R)  30e 3,4-DiClPh Oortho H H 1 CH₂CO0H (−)  30f 3,4-DiClPh O ortho H H 1 CH₂COOH (+)  20a3,4-DiClPh O ortho H H 1 CH₂CONH₂ (−)  20b 3,4-DiClPh O ortho H H 1CH₂CONH₂ (+)  30b 3,4-DiClPh O ortho H H 2 CH₂COOH 112a 3,4-DiClPh Oortho H H 1 CH₂CONHCH₃ 112b 3,4-DiClPh O ortho H H 1 CH₂CON(C₂H₅)₂  30f3,4-DiClPh O ortho H H 0 CH₂CON(CH₃)₂  30g 3,4-DiClPh O ortho H H 1CH₂CON(CH₃)₂Ph = phenyl, ClPh = chlorophenyl, DiClPh = di-chlorophenyl, FPh =Fluoprophenyl.*Position: the position refers to the position of the ArX lateral sidechain as compared to —CH₂—S(O)_(q)—Y—R¹ group on the central benzylring.

-   -   Ortho is position 2′, meta is position 3′ and para is position        4′.

36. A use of a compound of formula (A)

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, OR²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,            C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered            heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,            arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,            NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and            S(O)_(y)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,        C(R²²)₂C(R²²)₂, CR²═CR²¹, C≡C;    -   Y is C₁-C₆ alkylene; or        -   (C₁-C₄ alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;    -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10        membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered        heterocyclo-alkylene; wherein said arylene, heteroarylene,        cycloalkylene, and heterocycloalkylene groups are optionally        substituted with one to three R²⁰ groups;    -   R¹ is selected from C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴,        C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³,        OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and        NR²¹S(O)₂NR¹²R¹³;        -   wherein said aryl groups are optionally substituted with one            to three R²⁰ groups;    -   R² and R³ are each independently selected from from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered        heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,        NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said        alkyl and aryl groups are optionally substituted with one to        three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are        optionally substituted with one to three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;        -   wherein said alkyl and aryl groups and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl;        -   wherein said alkyl, aryl and arylalkyl groups are optionally            substituted with one to three R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl        optionally substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl,        phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²²,        OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,        OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and        C₁-C₆ alkyl;    -   R²² at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   m is 0 or 1;    -   n is 0 or 1;    -   q is 0, 1, or 2;    -   y is 0, 1, or 2;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof,        for the manufacture of a medicament useful for treating a        disease or a disorder selected from the group consisting of        sleepiness associated with narcolepsy, obstructive sleep apnea        or shift work disorder; Parkinson's disease; Alzheimer's        disease; attention deficit disorder; attention deficit        hyperactivity disorder; depression; and fatigue.

37. The use according to claim 36 for the manufacture of a medicamentuseful for the treatment of sleepiness associated with narcolepsy.

38. A use of a compound of formula (A)

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, R²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,            C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered            heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,            arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,            NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and            S(O)_(y)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,        C(R²²)₂, C(R²²)₂, CR²¹═CR²¹, C≡C;    -   Y is C₁-C₆ alkylene; or        -   (C₁-C₄ alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;    -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10        membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered        heterocyclo-alkylene; wherein said arylene, heteroarylene,        cycloalkylene, and heterocycloalkylene groups are optionally        substituted with one to three R²⁰ groups;    -   R¹ is selected from C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴,        C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³,        OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and        NR²¹S(O)₂NR¹²R¹³;        -   wherein said aryl groups are optionally substituted with one            to three R²⁰ groups;    -   R² and R³ are each independently selected from from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered        heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,        NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said        alkyl and aryl groups are optionally substituted with one to        three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are        optionally substituted with one to three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;        -   wherein said alkyl and aryl groups and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl;        -   wherein said alkyl, aryl and arylalkyl groups are optionally            substituted with one to three R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl        optionally substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl,        phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²²,        OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,        OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and        C₁-C₆ alkyl;    -   R²² at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   m is 0 or 1;    -   n is 0 or 1;    -   q is 0, 1, or 2;    -   y is 0, 1, or 2;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof,        for the manufacture of a medicament useful for the treatment of        a sleep-affecting disease or disorder in order to promote        wakefulness.

39. A use of a compound of formula (A)

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, OR²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,            C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered            heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,            arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,            NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and            S(O)_(y)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R ²²)₂C—O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,        C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C;    -   Y is C₁-C₆ alkylene; or        -   (C₁-C₄ alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;    -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10        membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered        heterocyclo-alkylene; wherein said arylene, heteroarylene,        cycloalkylene, and heterocycloalkylene groups are optionally        substituted with one to three R²⁰ groups;    -   R¹ is selected from C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴,        C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³,        OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and        NR²¹S(O)₂NR¹²R¹³;        -   wherein said aryl groups are optionally substituted with one            to three R²⁰ groups;    -   R² and R³ are each independently selected from from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered        heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,        NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said        alkyl and aryl groups are optionally substituted with one to        three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are        optionally substituted with one to three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;        -   wherein said alkyl and aryl groups and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl;        -   wherein said alkyl, aryl and arylalkyl groups are optionally            substituted with one to three R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl        optionally substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl,        phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²²,        OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,        OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and        C₁-C₆ alkyl;    -   R²² at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   m is 0 or 1;    -   n is 0 or 1;    -   q is 0, 1, or 2;    -   y is 0, 1, or 2;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof,        for the manufacture of a medicament useful for treating a        neurological disease or disorder selected from Parkinson's        disease; Alzheimer disease; attention deficit disorder;        attention deficit hyperactivity disorder; depression; and        fatigue associated with a neurological disease or disorder.

40. A pharmaceutical composition comprising a compound of formula (A)

wherein:

-   -   Ar is independantly selected from C₆-C₁₀ aryl and 5 to        10-membered heteroaryl wherein:        -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with            one to three groups selected from F, Cl, Br, I, OR²², OR²⁵,            NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,            C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered            heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,            arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,            NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and            S(O)_(y)R²²;    -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,        NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,        C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C;    -   Y is C₁-C₆ alkylene; or        -   (C₁-C₄ alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;    -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10        membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered        heterocyclo-alkylene; wherein said arylene, heteroarylene,        cycloalkylene, and heterocycloalkylene groups are optionally        substituted with one to three R²⁰ groups;    -   R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,        OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,        NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;        -   wherein said aryl groups are optionally substituted with one            to three R²⁰ groups;    -   R² and R³ are each independently selected from from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered        heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,        C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,        NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆        alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said        alkyl and aryl groups are optionally substituted with one to        three R²⁰ groups;    -   R¹¹ at each occurrence is independently selected from H, C₁-C₆        alkyl, and C₆-C₁₀ aryl;        -   wherein said alkyl and aryl groups are optionally            substituted with one to three R²⁰ groups;    -   R¹² and R¹³ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen        to which they are attached, form a 3-7 membered heterocyclic        ring;        -   wherein said alkyl group and heterocyclic ring are            optionally substituted with one to three R²⁰ groups;    -   R¹⁴ at each occurrence is independently selected from C₁-C₆        alkyl, C₆-C₁₀ aryl, and arylalkyl;        -   wherein said alkyl, aryl and arylalkyl groups are optionally            substituted with one to three R groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl        optionally substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl,        phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²²,        OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,        OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;    -   R²¹ at each occurrence is independently selected from H and C₁C₆        alkyl;    -   R²² at each occurrence is independently selected from H C₁-C₆        alkyl, and C₆-C₁₀ aryl;    -   R²³ and R²⁴ at each occurrence are each independently selected        from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together        with the nitrogen to which they are attached, form a 3-7        membered heterocyclic ring;    -   R²⁵ at each occurrence is independently the residue of an amino        acid after the hydroxyl group of the carboxyl group is removed;    -   m is 0 or 1;    -   n is 0 or 1;    -   q is 0, 1, or 2;    -   y is 0, 1, or 2;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof,        in admixture with one or more pharmaceutically acceptable        excipients.

41. A method for preparing a compound of claims 1 to 35, comprising thesteps of:

-   -   i) reacting a thiouronium compound (E) with a reactant of        structure LG-YR¹ to form a compound of formula (I):        wherein Ar, X, R², R³, Y, R¹ are as defined in claim 1, q=0 and        LG represents a leaving group; and optionally    -   ii) isolating the formed compound of formula (I).

42. The method of claim 41, wherein step i) comprises:

-   -   a) converting the compound of formula (E) into the corresponding        thiol compound; and    -   b) reacting the obtained thiol compound with the reactant        LG-Y—R¹.

43. The method of claims 41 or 42, wherein the compound (E) is formed byreacting the compound (D) with thiourea and a suitable acid HA:

-   -   wherein Ar, X, R², R³ are as defined in claim 1.

44. The method of claim 43, wherein the compound (D) is formed byreacting a compound (C) with a suitable reducing agent:

-   -   wherein Ar, X, R², R³ are as defined in claim 1 and W is C(═O)H        or COOH.

45. The method according to claim 44, wherein compound (C) is formed byreacting a compound (A) with a compound (B):

46. The method according to any of claims 41 to 45, wherein the compoundformed at step i) is a compound of formula (I) wherein q is 0, R¹ isCOOR, and R represents H or (C₁-C₆) alkyl:

47. The method according to claim 46 fuirther comprising:

-   -   a1) reacting the carboxylic acid or ester of formula (I) with an        appropriate amine of general structure NHR¹²R¹³, wherein R¹² and        R¹³ are as defined in claim 1; and optionally    -   b1) isolating the obtained compound of formula (I) wherein R¹ is        C(═O)NR¹²R¹³.

48. The method of any of claims 46 or 47 further comprising:

-   -   a2) oxidizing the compound of formula (I) wherein q is 0; and        optionally    -   b2) isolating the obtained compound of formula (I) wherein q is        1 or 2.

Although the present invention has been described in considerabledetail, those skilled in the art will appreciate that numerous changesand modifications may be made to the embodiments and preferredembodiments of the invention and that such changes and modifications maybe made without departing from the spirit of the invention. It istherefore intended that the appended claims cover all equivalentvariations as fall within the scope of the invention.

1. A compound of formula (A):

wherein: Ar is independantly selected from C₆-C₁₀ aryl and 5 to10-membered heteroaryl wherein: C₆-C₁₀ aryl and heteroaryl areoptionally substituted with one to three groups selected from F, Cl, Br,I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl,5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², andS(O)_(y)R²²; X is O, S(O)_(y), N(R¹⁰) OC(R²²)₂, (R²²)₂CO, C(R²²)₂NR²¹,NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; Y is C₁-C₆ alkylene; or (C₁-C₄alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n); wherein said alkylene groups areoptionally substituted with one to three R²⁰ groups; Z is O, NR^(10A),S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene; wherein saidarylene, heteroarylene, cycloalkylene, and heterocycloalkylene groupsare optionally substituted with one to three R²⁰ groups; R¹ is selectedfrom NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, andNR²¹S(O)₂NR¹²R¹³; wherein said aryl groups are optionally substitutedwith one to three R²⁰ groups; R² and R³ are each independently selectedfrom from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 memberedheterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; R¹⁰ and R^(10A) are eachindependently selected from H, C₁-C₆ alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, andS(O)_(y)R¹⁴; wherein said alkyl and aryl groups are optionallysubstituted with one to three R²⁰ groups; R¹¹ at each occurrence isindependently selected from H, C₃-C₇ alkyl and C₆-C₁₀ aryl; wherein saidalkyl and aryl group are optionally substituted with one to three R²⁰groups; R¹² and R¹³ at each occurrence are each independently selectedfrom H, C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to whichthey are attached, form a 3-7 membered heterocyclic ring; wherein saidalkyl group and heterocyclic ring are optionally substituted with one tothree R²⁰ groups; R¹⁴ at each occurrence is independently selected fromC₁-C₆ alkyl, C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl andarylalkyl groups are optionally substituted with one to three R²⁰groups; R²⁰ at each occurrence is independently selected from F, Cl, Br,I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionallysubstituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 memberedheteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;R²¹ at each occurrence is independently selected from H and C₁-C₆ alkyl;R²² at each occurrence is independently selected from H, C₁-C₆ alkyl,and C₆-C₁₀ aryl; R²³ and R²⁴ at each occurrence are each independentlyselected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, togetherwith the nitrogen to which they are attached, form a 3-7 memberedheterocyclic ring; R²⁵ at each occurrence is independently the residueof an amino acid after the hydroxyl group of the carboxyl group isremoved; m is 0 or 1; n is 0 or 1; q is 0, 1, or 2; y is 0, 1, or 2;with the exclusion of the compounds wherein: Y is C₂ alkylenesubstituted with one to three C₁-C₆ alkylene and/or NR²³R²⁴ and/orNR²¹CO₂R²²; and R¹ is C(═O)NR¹²R¹³. and with the exclusion of thecompound:tetrahydro-2-[[{4-(phenylthio)phenyl]methyl}thio]acetyl]-2H-1,2-oxazine;and the stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 2. The compoundaccording to claim 1, wherein: Y is C₁-C₆ alkylene; (C₁-C₄alkylene)_(m)—Z¹—(C₁-C₄ alkylene)_(n); C₁-C₄ alkylene-Z²—C₁-C₄ alkylene;wherein said alkylene groups are optionally substituted with one tothree R²⁰ groups; Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 memberedheteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene;wherein said arylene, heteroarylene, cycloalkylene, andheterocycloalkylene groups are optionally substituted with one to threeR²⁰ groups; Z² is O NR^(10A), or S(O)_(y).
 3. The compound according toclaim 1 wherein q is
 1. 4. The compound according to claim 1 wherein R¹is H.
 5. The compound according to claim 1 wherein R¹ is selected fromNR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, andNR²¹S(O)₂NR¹²R¹³.
 6. The compound according to claim 1 wherein R¹ isselected from NR¹²R¹³; NR²¹C(═O)R¹⁴; C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³; andNR²¹C(═O)NR¹²R¹³.
 7. The compound according to claim 6 wherein R¹ isC(═O)NR¹²R¹³.
 8. The compound according to claim 7 wherein R¹² and R¹³are each independently selected from H and C₁-C₆ alkyl.
 9. The compoundaccording to claim 7 wherein R¹² and R¹³ together with the nitrogen towhich they are attached, form a 3-7 membered heterocyclic ring, whereinsaid heterocyclic ring is optionally substituted with one R²⁰ group. 10.The compound according to claim 5 wherein R¹ is selected from C(═O)R¹⁴,CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, andNR²¹S(O)₂NR¹²R¹³.
 11. The compound according to claim 1 wherein X is O,S(O)_(y), N(R¹⁰).
 12. The compound according to claim 1 wherein X isOC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O),S(O)₂NR²², NR²²S(O)₂, C(R²²)₂C(R²²)₂.
 13. The compound according toclaim 12 wherein X is OC(R²²)₂, C(R²²)₂NR²¹, C(═O)N(R²¹), S(O)₂—NR²².14. The compound according to claim 1 wherein Y is C₁-C₆ alkylene. 15.The compound according to claim 14 wherein Y is CH₂.
 16. The compoundaccording to claim 2 wherein Y is (C₁-C₄ alkylene)_(m)—Z¹—(C₁-C₄alkylene)_(n).
 17. The compound according to claim 16 wherein Z¹ isC₆-C₁₀ arylene or C₃-C₆ cycloalkylene.
 18. The compound according toclaim 17 wherein Z¹ is phenylene.
 19. The compound according to claim 16wherein Z¹ is 5-10 membered heteroarylene or 3-6 memberedheterocycloalkylene.
 20. The compound according to claim 16 wherein Z¹is CR²¹═CR²¹ or C≡C.
 21. The compound according to claim 2 wherein Y isC₁-C₄ alkylene-Z²—C₁-C₄ alkylene.
 22. The compound according to claim 21wherein Z² is O.
 23. The compound according to claim 1 with thestructure:

wherein: Ar is independantly selected from C₆-C₁₀ aryl and 5 to10-membered heteroaryl wherein: C₆-C₁₀ aryl and heteroaryl areoptionally substituted with one to three groups selected from F, Cl, Br,I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, C₁-C₆ alkyl, phenyl, arylalkyl,and C(═O)R²²; X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂; Y isC₁-C₆alkylene; C₁-C₄ alkylene-Z¹—(C₁-C₄ alkylene)_(n); or C₁-C₄alkylene-Z²—C₁-C₄ alkylene; wherein said alkylene groups are optionallysubstituted with one to three R²⁰ groups; Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀arylene, 5-10 membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6membered heterocycloalkylene; Z² is O, NR^(10A), or S(O)_(y); R¹ isselected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, andNR²¹S(O)₂NR¹²R¹³; R² and R³ are each independently selected from F, Cl,Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5or 6 membered heteroaryl, arylalkyl, C(═O)R²²; R¹⁰ and R^(10A) are eachindependently selected from H, C₁-C₆ alkyl, C(═O)R¹⁴, and S(O)_(y)R¹⁴;wherein said alkyl groups are optionally substituted with one to threeR²⁰ groups; R¹¹ at each occurrence is independently selected from H orC₃-C₇ alkyl, wherein said alkyl group is optionally substituted with oneto three R²⁰ groups; R¹² and R¹³ at each occurrence are eachindependently selected from H, and C₁-C₆ alkyl, or R¹²and R¹³, togetherwith the nitrogen to which they are attached, form a 3-7 memberedheterocyclic ring; wherein said alkyl group and heterocyclic ring areoptionally substituted with one to three R²⁰ groups; R¹⁴ at eachoccurrence is independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl, andarylalkyl; wherein said alkyl, aryl and arylalkyl groups are optionallysubstituted with one to three R²⁰ groups; R²⁰ at each occurrence isindependently selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH,NO₂, CN, CF₃, phenyl, benzyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;R²¹ at each occurrence is independently selected from H and C₁-C₆ alkyl;R²² at each occurrence is independently selected from H, C₁-C₆ alkyl;and C₆-C₁₀ aryl; R²³ and R²⁴ at each occurrence are each independentlyselected from H, and C₁-C₆ alkyl, or R²³ and R²⁴, together with thenitrogen to which they are attached, form a 3-7 membered heterocyclicring; R²⁵ at each occurrence is independently the residue of an aminoacid after the hydroxyl group of the carboxyl group is removed; n is 0or 1; y is 0, 1, or 2; and the stereoisomeric forms, mixtures ofstereoisomeric forms or pharmaceutically acceptable salts forms thereof.24. The compound according to claim 23 wherein: Y is C₁-C₆ alkylene,C₁-C₄ alkylene-Z¹—C₁-C₄ alkylene, or C₁-C₄ alkylene-Z²—C₁-C₄ alkylene,wherein said alkylene groups are optionally substituted with one tothree C₁-C₆ alkyl groups; Z¹ is CR²¹═CR²¹, C≡C, or phenyl; Z² is O,NR^(10A), or S(O)_(y); X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O,C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂;and R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, andC(═O)NR¹²R¹³.
 25. The compound according to claim 24 wherein R¹ isC(═O)NR¹²R¹³.
 26. The compound according to claim 25 having thestructure of formula (Ib):


27. The compound according to claim 26 wherein X is O, S(O)_(y), N(R¹⁰),OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O),S(O)₂—NR²², NR²²S(O)₂.
 28. The compound according to claim 27 wherein Xis O, S(O)_(y), NH.
 29. The compound according to claim 27 wherein X isOCH₂, CH₂O, CH₂NH, NHCH₂, C(═O)NH, NHC(═O), S(O)₂NH, NHS(O)₂.
 30. Thecompound according to claim 27 wherein X is NH, O—CH₂, CH₂NH, C(═O)NH,or S(O)₂—NH.
 31. The compound according to any of claims 1, 23, or 26wherein R² and R³ are each independently selected from F, Cl, Br, I,OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5 or 6membered heteroaryl, arylalkyl, C(═O)R²².
 32. The compound according toclaim 26 wherein Y is C₁-C₆ alkylene.
 33. The compound according toclaim 32 wherein Y is CH₂.
 34. The compound according to claim 26wherein Y is (C₁-C₄ alkylene)_(n)—Z¹—C₁-C₄ alkylene and Z¹ is phenyl,5-6 membered heteroarylene, CR²¹═CR²¹, or C≡C.
 35. The compoundaccording to claim 1 selected in accordance with the following table,wherein: TABLE 1

Ex. n° Ar X Position* R² R³ q Y—R¹  13 3,4-DiClPh O para H H 0 CH₂CO-N-piperazinyl-N-Boc  14 3,4-DiClPh O para H H 0 CH₂CO-N-piperazinyl  193,4-DiClPh O para H H 1 CH₂CO-N-piperazinyl  16 4-ClPh S para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  23 4-ClPh S para H H 1CH₂CO-1-(4-acetyl)- piperazinyl  24 4-ClPh SO para H H 1CH₂CO-1-(4-acetyl)- piperazinyl  29 Ph O para H H 1 CH₂CONHCHMe₂ Ph Ometa H H 0 CH₂CO-N- pyrrolidinyl  31 Ph O meta H H 1 CH₂CO-N-pyrrolidinyl Ph O meta H H 0 CH₂CONH₂  32 Ph O meta H H 1 CH₂CONH₂ Ph Ometa H H 0 CH₂CONMe₂  33 Ph O meta H H 1 CH₂CONMe₂ Ph O meta H H 0CH₂CONHCHMe₂  34 Ph O meta H H 1 CH₂CONHCHMe₂ Ph O meta H H 0CH₂CO-1-(4-acetyl)- piperazinyl  35 Ph O meta H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 4-OCH₃Ph O para H H 0 CH₂CONH₂  36 4-OCH₃Ph O para H H 1CH₂CONH₂ 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  374-OCH₃Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para HH 0 CH₂CO-N-piperazinyl  38 4-OCH₃Ph O para H H 1 CH₂CO-N-piperazinyl3,4-DiClPh O para H H 0 CH₂CONH₂  39 3,4-DiClPh O para H H 1 CH₂CONH₂ 11 3,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  223,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl  27 3,4-DiClPh Opara H H 2 CH₂CO-1-(4-acetyl)- piperazinyl  30 3,4-DiClPh O para H H 1CH₂COOH  15 3,4-DiClPh O ortho H H 0 CH₂CONH₂  20 3,4-DiClPh O ortho H H1 CH₂CONH₂ 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  403,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh Opara H H 0 CH₂CO-1-(4- carboxamide)- piperazinyl  41 3,4-DiClPh O para HH 1 CH₂CO-1-(4- carboxamide)- piperazinyl 4-OCH₃Ph O ortho H H 0CH₂CONH₂  42 4-OCH₃Ph O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0CH₂CONH₂  43 2-ClPh O para H H 1 CH₂CONH₂ 4-OHPh O ortho H H 0 CH₂CONH₂ 44 4-OHPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho H H 0 CH₂CONH₂  452-ClPh O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  46 2-ClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-ClPh O para H H 0 CH₂CO-N-piperazinyl  47 2-ClPh O para H H 1CH₂CO-N-piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 48 4-FPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl  95 4-FPh O paraH H 2 CH₂CO-1-(4-acetyl)- piperazinyl  96 4-FPh O para H H 1 CH₂COOH4-FPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  49 4-FPh O ortho HH 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-FPh O para H H 0 CH₂CONH₂  504-FPh O para H H 1 CH₂CONH₂ 4-FPh O ortho H H 0 CH₂CONH₂  51 4-FPh Oortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CONH₂  52 2-Naphthyl Oortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  53 2-Naphthyl O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-Naphthyl O para H H 0 CH₂CONH₂  54 2-Naphthyl O para H H 1 CH₂CONH₂2-BiPh O para H H 0 CH₂CONH₂  55 2-BiPh O para H H 1 CH₂CONH₂ 2-BiPh Oortho H H 0 CH₂CONH₂  56 2-BiPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho HH 0 CH₂CO-1-(4-acetyl)- piperazinyl  57 2-ClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2-Naphthyl O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  58 2-Naphthyl O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2-BiPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl  59 2-BiPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl2-BiPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl  60 2-BiPh O para HH 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-ClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  61 4-ClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para H H 0CH₂CO-1-(4-methyl)- piperazinyl  62 4-OCH₃Ph O para H H 1CH₂CO-1-(4-methyl)- piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-1-(4-ethylcarboxylate)- piperazinyl  63 3,4-DiClPh O para H H 1 CH₂CO-1-(4-ethylcarboxylate)- HHpiperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-hydroxyethyl)- piperazinyl  64 4-FPh O para H H 1 CH₂CO-1-(4-hydroxyethyl)- piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-hydroxyethyl)- piperazinyl  65 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4-hydroxyethyl)- piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-methyl)-piperazinyl  66 4-FPh O para H H 1 CH₂CO-1-(4-methyl)- piperazinyl4-ClPh O para H H 0 CH₂CONH₂  67 4-ClPh O para H H 1 CH₂CONH₂ 4-FPh Opara H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  68 4-FPh O para HH 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-OCH₃Ph O para H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  69 4-OCH₃Ph O para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-ClPh S para H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  70 4-ClPh S para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  71 4-ClPh SO para H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 3,4-DiClPh O ortho H H 0CH₂CO-1-(4- ethylcarboxylate)- piperazinyl  72 3,4-DiClPh O ortho H H 1CH₂CO-1-(4- ethylcarboxylate)- piperazinyl Ph O ortho H H 0 CH₂CONH₂  97Ph O ortho H H 1 CH₂CONH₂ Ph O ortho H H 0 CH₂CO-N- pyrrolidinyl  98 PhO ortho H H 1 CH₂CO-N- pyrrolidinyl Ph O ortho H H 0 CH₂CONMe₂  99 Ph Oortho H H 1 CH₂CONMe₂ Ph O para H H 0 CH₂CONMe₂ 100 Ph O para H H 1CH₂CONMe₂ Ph O para H H 0 CH₂CO-N- pyrrolidinyl 101 Ph O para H H 1CH₂CO-N- pyrrolidinyl Ph O para H H 0 CH₂CONH₂ 102 Ph O para H H 1CH₂CONH₂ Ph O ortho H H 0 CH₂CONHCH₂CN 103 Ph O ortho H H 1 CH₂CONHCH₂CNPh O ortho H H 0 CH₂CONHCHMe₂ 104 Ph O ortho H H 1 CH₂CONHCHMe₂ Ph Oortho H H 0 CH₂CONHCMe₃ 105 Ph O ortho H H 1 CH₂CONHCMe₃ Ph O ortho H H0 CH₂CO-1-(4- hydroxy)-piperidinyl 106 Ph O ortho H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl  12 Ph O ortho H H 0 CH₂CONH(CH₂)₂OH  21 Ph O orthoH H 1 CH₂CONH(CH₂)₂OH Ph O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl107 Ph O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl Ph O meta H H 0CH₂CONH(CH₂)₂OH 108 Ph O meta H H 1 CH₂CONH(CH₂)₂OH Ph O meta H H 0CH₂CO-1-(4- hydroxy)-piperidinyl 109 Ph O meta H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl 110 Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl111 Ph O para H H 1 CH₂CONH(CH₂)₂OH 112 Ph O para H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl 113 4-ClPh CONH ortho H H 1 CH₂CONH₂ 1143,4-DiOCH₃Ph CONH ortho H H 1 CH₂CONH₂ 115 2-Naphthyl CONH ortho H H 1CH₂CONH₂ 116 4-ClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 1173,4DiFPh CONH ortho H H 1 CH₂CONH₂ 118 2,4-DiOCH₃Ph CONH ortho H H 1CH₂CONH₂ 119 3,4,5- CONH ortho H H 1 CH₂CONH₂ TriOCH₃Ph 120 3,4-DiOCH₃PhCONH meta H H 1 CH₂CONH₂ 121 2,4-DiOCH₃Ph CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 122 3,4-DiOCH₃Ph CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 123 4-FPh CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 124 3,4-DiClPh CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 125 2,4-DiOCH₃Ph CONH meta H H 1CH₂CONH₂ 126 4-FPh CONH meta H H 1 CH₂CONH₂ 127 3,4-DiClPh CONH meta H H1 CH₂CONH₂ 7 4-ClPh O para H H 0 CH₃ 8 4-ClPh O para H H 1 CH₃ 9 4-ClPhO para H H 1 CH₂[4(4- ClPhenoxy)phenyl] 3,4-DiClPh O para H H 0 CH₃  103,4-DiClPh O para H H 1 CH₃ 4-ClPh S ortho H H 0 CH₂CO-N-piperazinyl  734-ClPh S ortho H H 1 CH₂CO-N-piperazinyl 2,3-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  74 2,3-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  75 2,5-DiCiPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0 CH₂CONH₂  762,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,3-DiClPh O ortho H H 0 CH₂CONH₂  772,3-DiClPh O ortho H H 1 CH₂CONH₂ 2,4-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  78 2,4-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  79 2,4-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O para H H 0 CH₂CONH₂  802,4-DiClPh O para H H 1 CH₂CONH₂ 2,4-DiClPh O ortho H H 0 CH₂CONH₂  812,4-DiClPh O ortho H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0CH₂CO-1-(4-acetyl)- piperazinyl  82 3,5-DiClPh O ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  83 3,5-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0 CH₂CONH₂  843,5-DiClPh O para H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0 CH₂CONH₂  853,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,5-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  86 2,5-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh S para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  87 3,4-DiClPh S para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh S para H H 0 CH₂CONH₂  882,5-DiClPh S para H H 1 CH₂CONH₂ 3,4-DiClPh S para H H 0 CH₂CONH₂  893,4-DiClPh S para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  90 2,3-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0CH₂CO-1-(4-acetyl)- piperazinyl  91 2,6-DiClPh O para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0 CH₂CONH₂  922,6-DiClPh O para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0 CH₂CONH₂  932,3-DiClPh O para H H 1 CH₂CONH₂  94 2,3-DiClPh O para H H 2 CH₂CONH₂135 Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 136 Ph NH para H H1 CH₂CO-1-(4-acetyl)- piperazinyl 134 4-OCH₃Ph NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 131 4-FPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 137 4-OCH₃Ph NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 138 4-FPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 139 4-ClPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 140 4-FPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 128 3,4-DiClPh CONH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 129 4-FPh CONH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 141 3,4-DiClPh NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 132 4-ClPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 147 4-FPh CH₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 133 3,4-DiClPh SO₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 148 3,4-DiClPh CH₂NH para H H 1CH₂CO-1-(4-acetyl)- piperazinyl 149 4-FPh CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 146 3,4-DiClPh CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 130 3,4-DiClPh SO₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 145 2-Furyl CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 144 2-Thienyl CH₂NH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 142 2-Thienyl CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 143 2-Furyl CONH ortho H H 1CH₂CO-1-(4-acetyl)- piperazinyl 152 Ph OCH₂ ortho H H 0 CH₂CONH₂ 153 PhOCH₂ ortho H H 1 CH₂CONH₂  17 4-ClPh O para 2′-Cl H 0CH₂CO-1-(4-acetyl)- piperazinyl  18 4-ClPh O para 2′-Cl H 0 CH₂CONH₂  254-ClPh O para 2′-Cl H 1 CH₂CO-1-(4-acetyl)- piperazinyl  26 4-ClPh Opara 2′-Cl H 1 CH₂CONH₂ 149a 3,4-DiClPh CONH para H H 1 CH₂CONH₂ 109a4-ClPh O ortho H H 1 CH₂CONH₂ 109b 3-Cl-4-FPh O ortho H H 1 CH₂CONH₂109c 4-Cl-3-FPh O ortho H H 1 CH₂CONH₂ 109d 3-Cl-4-FPh O ortho H H 2CH₂CONH₂  10a 4-ClPh O ortho 4′-Cl H 0 CH₂COOH  18a 4-ClPh O ortho 4′-ClH 0 CH₂CONH₂  27a 4-ClPh O ortho 4′-Cl H 1 CH₂CONH₂  27b 4-ClPh O ortho4′-Cl H 2 CH₂CONH₂ 109e 3,4-DiFPh O ortho 4′-Cl H 1 CH₂CONH₂ 109f3,4-DiClPh O ortho H H 2 CH₂CONH₂  30a 3,4-DiClPh O ortho H H 1 CH₂COOH 30d 3,4-DiClPh O ortho H H 0 CH₂COOMenthyl (1R,2S,5R)  30e 3,4-DiClPh Oortho H H 1 CH₂CO0H (−)  30f 3,4-DiClPh O ortho H H 1 CH₂COOH (+)  20a3,4-DiClPh O ortho H H 1 CH₂CONH₂ (−)  20b 3,4-DiClPh O ortho H H 1CH₂CONH₂ (+)  30b 3,4-DiClPh O ortho H H 2 CH₂COOH 112a 3,4-DiClPh Oortho H H 1 CH₂CONHCH₃ 112b 3,4-DiClPh O ortho H H 1 CH₂CON(C₂H₅)₂  30f3,4-DiClPh O ortho H H 0 CH₂CON(CH₃)₂  30g 3,4-DiClPh O ortho H H 1CH₂CON(CH₃)₂Ph = phenyl, ClPh = chlorophenyl, DiClPh = di-chlorophenyl, FPh =Fluoprophenyl.*Position: the position refers to the position of the ArX lateral sidechain as compared to —CH₂—S(O)_(q)—Y—R¹ group on the central benzylring.Ortho is position 2′, meta is position 3′ and para is position 4′.


36. A method of treating a disease or a disorder selected from the groupconsisting of sleepiness associated with narcolepsy; obstructive sleepapnea; shift work disorder; Parkinson's disease; Alzheimer's disease;attention deficit disorder; attention deficit hyperactivity disorder;depression; and fatigue, comprising administering to a patient in needthereof a compound of formula (A)

wherein: Ar is independantly selected from C₆-C₁₀ aryl and 5 to10-membered heteroaryl wherein: C₆-C₁₀ aryl and heteroaryl areoptionally substituted with one to three groups selected from F, Cl, Br,I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl,5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², andS(O)_(y)R²²; X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; Y is C₁-C₆ alkylene; or (C₁-C₄alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n); wherein said alkylene groups areoptionally substituted with one to three R²⁰ groups; Z is O, NR^(10A),S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,C₃-C₆ cycloalkylene, or 3-6 membered heterocyclo-alkylene; wherein saidarylene, heteroarylene, cycloalkylene, and heterocycloalkylene groupsare optionally substituted with one to three R²⁰ groups; R¹ is selectedfrom C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³; wherein said aryl groups areoptionally substituted with one to three R²⁰ groups; R² and R³ are eachindependently selected from from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 memberedheteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and arylgroups are optionally substituted with one to three R²⁰ groups; R¹¹ ateach occurrence is independently selected from H, C₁-C₆ alkyl, andC₆-C₁₀ aryl; wherein said alkyl and aryl groups are optionallysubstituted with one to three R²⁰ groups; R¹² and R¹³ at each occurrenceare each independently selected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, orR¹² and R¹³, together with the nitrogen to which they are attached, forma 3-7 membered heterocyclic ring; wherein said alkyl and aryl groups andheterocyclic ring are optionally substituted with one to three R²⁰groups; R¹⁴ at each occurrence is independently selected from C₁-C₆alkyl, C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl andarylalkyl groups are optionally substituted with one to three R²⁰groups; R²⁰ at each occurrence is independently selected from F, Cl, Br,I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionallysubstituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 memberedheteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;R²¹ at each occurrence is independently selected from H and C₁-C₆ alkyl;R²² at each occurrence is independently selected from H, C₁-C₆ alkyl,and C₆-C₁₀ aryl; R²³ and R²⁴ at each occurrence are each independentlyselected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, togetherwith the nitrogen to which they are attached, form a 3-7 memberedheterocyclic ring; R²⁵ at each occurrence is independently the residueof an amino acid after the hydroxyl group of the carboxyl group isremoved; m is 0 or 1; n is 0 or 1; q is 0, 1, or 2; y is 0, 1, or 2; ora stereoisomeric form, mixture of stereoisomeric forms, or apharmaceutically acceptable salts form thereof.
 37. The method accordingto claim 36 wherein the disease or disorder is sleepiness associatedwith narcolepsy.
 38. A method for the treatment of a sleep-affectingdisease or disorder in order to promote wakefulness comprisingadministering to a patient in need thereof a compound according to claim1 or a stereoisomeric form, mixture of stereoisomeric forms, or apharmaceutically acceptable salt form thereof.
 39. A method for treatinga neurological disease or disorder selected from Parkinson's disease;Alzheimer disease; attention deficit disorder; attention deficithyperactivity disorder; depression; and fatigue associated with aneurological disease or disorder, comprising administering to a patientin need thereof a compound according to claim 1 or a stereoisomericform, mixture of stereoisomeric forms, or a pharmaceutically acceptablesalt form thereof.
 40. A pharmaceutical composition comprising acompound of formula (A)

wherein: Ar is independantly selected from C₆-C₁₀ aryl and 5 to10-membered heteroaryl wherein: C₆-C₁₀ aryl and heteroaryl areoptionally substituted with one to three groups selected from F, Cl, Br,I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl,5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², andS(O)_(y)R²²; X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; Y is C₁-C₆ alkylene; or (C₁-C₄alkylene)_(m)—Z—(C₁-C₄ alkylene)_(n); wherein said alkylene groups areoptionally substituted with one to three R²⁰ groups; Z is O, NR^(10A),S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,C₃-C₆ cycloalkylene, or 3-6 membered heterocyclo-alkylene; wherein saidarylene, heteroarylene, cycloalkylene, and heterocycloalkylene groupsare optionally substituted with one to three R²⁰ groups; R¹ is selectedfrom NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, andNR²¹S(O)₂NR¹²R¹³; wherein said aryl groups are optionally substitutedwith one to three R²⁰ groups; R² and R³ are each independently selectedfrom from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 memberedheterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; R¹⁰ and R^(10A) are eachindependently selected from H, C≡C₆ alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, andS(O)_(y)R¹⁴; wherein said alkyl and aryl groups are optionallysubstituted with one to three R²⁰ groups; R¹¹ at each occurrence isindependently selected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl; whereinsaid alkyl and aryl groups are optionally substituted with one to threeR²⁰ groups; R¹² and R¹³ at each occurrence are each independentlyselected from H, C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogento which they are attached, form a 3-7 membered heterocyclic ring;wherein said alkyl group and heterocyclic ring are optionallysubstituted with one to three R²⁰ groups; R¹⁴ at each occurrence isindependently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl, and arylalkyl;wherein said alkyl, aryl and arylalkyl groups are optionally substitutedwith one to three R²⁰ groups; R²⁰ at each occurrence is independentlyselected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃,C₁-C₆ alkyl optionally substituted by one to three OH, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl,5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², andS(O)_(y)R²²; R²¹ at each occurrence is independently selected from H andC₁-C₆ alkyl; R²² at each occurrence is independently selected from HHC₁-C₆ alkyl, and C₆-C₁₀ aryl; R²³ and R²⁴ at each occurrence are eachindependently selected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ andR²⁴, together with the nitrogen to which they are attached, form a 3-7membered heterocyclic ring; R²⁵ at each occurrence is independently theresidue of an amino acid after the hydroxyl group of the carboxyl groupis removed; m is 0 or 1; n is 0 or 1; q is 0, 1, or 2; y is 0, 1, or 2;and the stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof, in admixture with oneor more pharmaceutically acceptable excipients.
 41. A method forpreparing a compound of claim 1, comprising the steps of: i. reacting athiouronium compound (E) with a reactant of structure LG-YR¹ to form acompound of formula (I):

wherein Ar, X, R², R³, Y, R¹ are as defined in claim 1, q=0 and LGrepresents a leaving group; and optionally ii) isolating the formedcompound of formula (I).
 42. The method of claim 41, wherein step i)comprises: c) converting the compound of formula (E) into thecorresponding thiol compound; and d) reacting the obtained thiolcompound with the reactant LG-Y—R′.
 43. The method of claim 42, whereinthe compound (E) is formed by reacting the compound (D) with thioureaand a suitable acid HA:

wherein Ar, X, R², R³ are as defined in claim
 1. 44. The method of claim43, wherein the compound (D) is formed by reacting a compound (C) with asuitable reducing agent:

wherein Ar, X, R², R³ are as defined in claim 1 and W is C(═O)H or COOH.45. The method according to claim 44, wherein compound (C) is formed byreacting a compound (A) with a compound (B):


46. The method according to claim 41, wherein the compound formed atstep i) is a compound of formula (I) wherein q is 0, R¹ is COOR, and Rrepresents H or (C₁-C₆) alkyl:


47. The method according to claim 46 further comprising: a1) reactingthe carboxylic acid or ester of formula (I) with an appropriate amine ofgeneral structure NHR¹²R¹³, wherein R¹² and R¹³ are as defined in claim1; and optionally b1) isolating the obtained compound of formula (I)wherein R¹ is C(═O)NR¹²R¹³.
 48. The method of claim 46 or 47 furthercomprising: a2) oxidizing the compound of formula (I) wherein q is 0;and optionally b2) isolating the obtained compound of formula (I)wherein q is 1 or 2.